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WO2025107035A1 - Formulation inhalable - Google Patents

Formulation inhalable Download PDF

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Publication number
WO2025107035A1
WO2025107035A1 PCT/AU2024/051244 AU2024051244W WO2025107035A1 WO 2025107035 A1 WO2025107035 A1 WO 2025107035A1 AU 2024051244 W AU2024051244 W AU 2024051244W WO 2025107035 A1 WO2025107035 A1 WO 2025107035A1
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WO
WIPO (PCT)
Prior art keywords
formulation
melatonin
inhalable
inhalable formulation
present
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/AU2024/051244
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English (en)
Inventor
David Andrew Lewis
Paul Michael Young
Robert David Johnson
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Morpheus Therapeutics Pty Ltd
Original Assignee
Morpheus Therapeutics Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2023903769A external-priority patent/AU2023903769A0/en
Application filed by Morpheus Therapeutics Pty Ltd filed Critical Morpheus Therapeutics Pty Ltd
Publication of WO2025107035A1 publication Critical patent/WO2025107035A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • This disclosure relates to an inhalable formulation comprising melatonin and, optionally, a cannabinoid. Furthermore, this disclosure relates to a metered dose inhaler containing the inhalable formulation and methods and uses of the inhalable formulation.
  • Melatonin secreted by the pineal gland, is an important hormone involved in the regulation of the circadian rhythm, including sleep-wake timing, blood pressure regulation, seasonal reproduction and others. Melatonin has been shown to modify immunity, the stress response, and certain aspects of the aging process. Melatonin has further been found to have antioxidant properties which may be of potential use for conditions in which oxidative stress is involved in the pathophysiologic processes. The multiplicity of actions and variety of biological effects of melatonin suggest the potential for a range of clinical and wellness-enhancing uses, especially considering that melatonin production steadily decreases with ageing and certain medical conditions, such as cardiovascular and neurodegenerative diseases.
  • the average melatonin profile shows an evening rise between around 8 pm and midnight, reaches peak values between around 2 am and 4 am and then drops to low daytime levels. Circulating nocturnal levels of melatonin are commonly 10 to 20 times higher than concentrations measured during the day.
  • this natural circadian rhythm is disrupted, for example in people suffering from chronic insomnia, jet lag or shift workers and in elderly subjects with low natural melatonin levels, several studies suggest that night-time melatonin administration can help induce sleep.
  • Melatonin has been successfully used to enhance sleep processes in elderly individuals with insomnia and in individuals with restless leg syndrome, REM sleep disorder behaviour, delayed sleep phase syndrome, manic patients with insomnia and in patients with fibromyalgia.
  • Melatonin supplements are mostly available for oral administration, such as tablets, capsules, liquid, lozenges, sublingual tablets, tea and timed release tablets.
  • it can take more than 30 minutes after administration for the blood plasma concentration of melatonin to reach its peak. This is due, in part, to the need for gastrointestinal absorption to occur before the melatonin is available in the bloodstream. Further, melatonin's oral bioavailability is poor and erratic.
  • the disclosure resides in an inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent which is traw -l,3,3,3-tetrafhioroprop-l-ene (HFO 1234ze).
  • the disclosure resides in a metered dose inhaler comprising an inhalable formulation, the inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the melatonin may be present at between about 0.01% w/w and about 0.5% w/w, or about 0.01% w/w and about 0.4% w/w, or about 0.01% w/w and about 0.3% w/w, or about 0.01% w/w and about 0.2% w/w, or 0.01% w/w and about 0.15% w/w, or between about 0.01% w/w and about 0.1% w/w, or at between about 0.025% w/w and about 0.1% w/w of the formulation.
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 250 pg/50 pL w/v, or between about 5 pg/50 pL w/v and about 200 pg/50 pL w/v, or between about 5 pg/50 pL w/v and about 150 pg/50 pL w/v, or between about 5 pg/50 pL w/v and about 100 pg/50 pL w/v, or between about 10 pg/50 pL w/v and about 250 pg/50 pL w/v, or between about 10 pg/50 pL w/v and about 200 pg/50 pL w/v, or between about 10 pg/50 pL w/v and about 150 pg/50 pL w/v, or between about 10 pg/50 pL w/v, or between about 10
  • the propellant may be present at an amount of at least 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, 80% w/w, 85% w/w, or 90% w/w, or 95% w/w of the entire formulation.
  • the Ci to Ce alcohol may be present at between l%-20% w/w, or between 1%-19% w/w, or between 1%-18% w/w, or between 1%-17% w/w, or between 1%- 16% w/w, or between 1%- 15% w/w, or between 1%- 14% w/w, or between 1%-13% w/w, or between 1%-12% w/w, or between 1%-11% w/w, or between l%-10% w/w, or between 2%-20% w/w, or between 2%-19% w/w, or between 2%-l 8% w/w, or between 2%-17% w/w, or between 2%-16% w/w, or between 2%-15% w/w of the formulation.
  • the Ci to Ce alcohol may be present at between 1%- 10% w/w, or between l%-8% w/w, or between l%-7% w/w, or between l%-6% w/w, or between l%-5% w/w.
  • the Ci to Ce alcohol may be present at around 5% w/w.
  • the Ci to Ce alcohol may be selected from a Ci to C4 alcohol, a C2 to C4 alcohol, and a C2 or C3 alcohol.
  • the Ci to Ce alcohol may be ethanol.
  • the inhalable formulation may be an inhalable solution.
  • the melatonin may be the only non-volatile component of the inhalable formulation or may be the only biologically active agent (in terms of treatment of sleep-related disorders) in the inhalable formulation or is the only component of the formulation which is a solid (when not dissolved or otherwise in any formulation or mixture) at room temperature.
  • the inhalable formulation may further comprise one or more cannabinoids.
  • the one or more cannabinoids may be selected from the group consisting of anandamide, 2-arachidonoylglycerol, cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichormevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabielsoin (CBE), cannabicyclol (CBL), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabinol (CBN
  • the one or more cannabinoids may be cannabidiol (CBD) or dronabinol.
  • the one or more cannabinoids may be cannabidiol (CBD) and dronabinol.
  • the one or more cannabinoids may be present in a total amount at between about 0.1% w/w and about 4.0% w/w, or between about 0.1% w/w and about 3.5% w/w, or between about 0.1% w/w and about 3.0% w/w, or between about 0.1% w/w and about 2.5% w/w, or between about 0.1% w/w and about 2.0% w/w, or between about 0.1% w/w and about 1.5% w/w, or between about 0.1% w/w and about 1.0% w/w, or at between about 0.1% w/w and about 0.9% w/w, or at between about 0.1% w/w and about 0.8% w/w of the formulation.
  • the one or more cannabinoids are present in a total amount at between about 0.2% w/w and about 4.0% w/w, or between about 0.2% w/w and about 3.5% w/w, or between about 0.2% w/w and about 3.0% w/w, or between about 0.2% w/w and about 2.5% w/w, or between about 0.2% w/w and about 2.0% w/w, or between about 0.2% w/w and about 1.5% w/w, or between about 0.2% w/w and about 1.0% w/w, or at between about 0.2% w/w and about 0.9% w/w, or at between about 0.2% w/w and about 0.8% w/w of the formulation.
  • the one or more cannabinoids are present in a total amount at between about 50 pg/50 pL w/v and about 2000 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 2000 pg/50 pL w/v, or at between about 150 pg/50 pL w/v and about 2000 pg/50 pL w/w, or at between about 200 pg/50 pL w/v and about 2000 pg/50 pL w/v, or at between about 50 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 150 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 150 pg
  • the inhalable formulation provides for a fine particle fraction of greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%.
  • the fine particle fraction may be measured under standard industry conditions and/or as described in the Examples section.
  • the inhalable formulation may comprise, consist of or consist essentially of : melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (UFO 1234ze); and, optionally, one or more cannabinoids, optionally one of delta-9-tetrahydrocannabinol (THC; dronabinol) and/or cannabidiol (CBD).
  • melatonin a Ci to Ce alcohol
  • a propellent which is traw -l,3,3,3-tetrafluoroprop-l-ene (UFO 1234ze)
  • cannabinoids optionally one of delta-9-tetrahydrocannabinol (THC; dronabinol) and/or cannabidiol (CBD).
  • the total mass of melatonin and any one or more cannabinoids per 50 pL metered dose of the formulation may be less than 1 mg, optionally less than 900 pg, or less than 800 pg, or less than 700 pg, or less than 600 pg, or less than 500 pg, or less than 450 pg.
  • the inhalable formulation may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the inhalable formulation may consist of or consist essentially of: melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; one or more cannabinoids, optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • melatonin optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation
  • a Ci to Ce alcohol optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation
  • one or more cannabinoids optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation
  • a propellent which is traw
  • the inhalable formulation may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; cannabidiol (CBD), optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the inhalable formulation may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; dronabinol, optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the inhalable formulation may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; dronabinol and cannabidiol (CBD), optionally present at a combined amount of between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the disclosure resides in a method of delivering melatonin to a subject including the steps of: providing the inhalable formulation of the first aspect; and allowing the subject to inhale the inhalable formulation, to thereby deliver the melatonin to the subject.
  • the inhalable formulation of the first aspect may be delivered to the subject by activation of a metered dose inhaler, preferably the metered dose inhaler of the second aspect.
  • the inhalable formulation may be delivered having a fine particle fraction of greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%.
  • the inhalable formulation may be delivered having a fine particle dose of melatonin of between about 10 pg and about 35 pg from a 50 pL metered dose.
  • the disclosure resides in a method of preventing or treating a disease, disorder or condition in a subject, comprising administering an effective amount of the inhalable formulation of the first aspect to the subject.
  • the disclosure resides in a use of the inhalable formulation of the first aspect in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.
  • the disclosure resides in a use of the inhalable formulation of the first aspect for the treatment or prevention of a disease, disorder or condition.
  • the disclosure resides in the inhalable formulation of the first aspect for use in the treatment or prevention of a disease, disorder or condition.
  • the disease, disorder or condition may be a sleep disorder.
  • the sleep disorder may involve difficulty falling asleep, remaining asleep, or excessive sleepiness.
  • the sleep disorder may be selected from the group consisting of insomnia; a circadian rhythm sleep disorder (CRSD), including jetlag and shift work sleep disorders; anxiety related sleep disorders; narcolepsy; bruxism; catathrenia; delayed sleep phase disorder (DSPD); fatal familial insomnia; hypopnea syndrome; idiopathic hypersomnia; Kleine-Levin syndrome; night terror; nocturia; parasomnias; periodic limb movements in sleep (PLMS); rapid eye movement sleep behavior disorder (RBD); restless legs syndrome (RLS); sleep apnoea; sleep paralysis; sleepwalking; somniphobia; hypersomnia; failure to wake-up feeling refreshed and rested or fatigue on waking; and related disorders.
  • CRSD circadian rhythm sleep disorder
  • CRSD circadian rhythm sleep disorder
  • CRSD circadian rhythm sleep disorder
  • CRSD circadian rhythm sleep disorder
  • CRSD circadian rhythm sleep disorder
  • CRSD circadian rhythm sleep disorder
  • CRSD circadian rhythm sleep disorder
  • FIG. 1 is a graphical representation of the drug delivery metrics determined by Next Generation Cascade Impactor (NGI) at 301/min sampling flow rate for melatonin formulations with 25 pg melatonin.
  • the formulations shown in FIG. 1 contained 25pg/50pl melatonin, 5% EtOH, HFA134a (NGI-1153 &I 154) and 25pg/50pl melatonin, 5% EtOH, HFO1234ze (NGI-1155&1156).
  • FIG. 2 is a graphical representation of the drug delivery metrics determined by Next Generation Cascade Impactor (NGI) at 301/min sampling flow rate for melatonin formulations with 50 pg melatonin.
  • the formulations shown in FIG. 2 contained 50pg/50pl melatonin, 10% EtOH, HFA134a (NGI-1157&1158) and 50pg/50pl melatonin, 10% EtOH, HFO1234ze (NGI-1159 and NGI-1160).
  • the formulation of the present invention comprising the components as described herein may, in another embodiment, consist of those components, or in another embodiment, consist essentially of those components.
  • the term “comprise” refers to the inclusion of the indicated components as well as the inclusion of other components, active agents, and pharmaceutically or physiologically acceptable carriers, excipients, emollients, stabilisers, etc., as are known in the industry.
  • the term “consisting essentially of’ refers to a formulation whose only main components are the recited components and the formulation excludes all further components that will materially affect the essential characteristics of the formulation. However, other compounds may be included which are not involved directly in giving the formulation the desired characteristics of the formulation.
  • treat or other forms of the word, such as “treated”, “treating”, or “treatment,” is meant to administer a composition or to perform a method in order to reduce or prevent a particular characteristic or event (e.g., sleep disorder).
  • control is used synonymously with the term “treat.”
  • the treatment does not necessarily provide therapy for the underlying pathology that is causing the sleep disorder sensation.
  • Treatment of a sleep disorder can be purely symptomatic.
  • treatment of a sleep disorder can include modifying or improving the sleep-wake cycle of a subject.
  • active agent or “active pharmaceutical ingredient” or “API” are used interchangeably, and refer to a pharmacological agent that can act locally or systemically in the body.
  • active agent includes agents that can be administered to a subject for the treatment or prevention of a disease, disorder or condition.
  • melatonin supplements are delivered orally via tablets, lozenges, or as a liquid. Because of the poor bioavailability of melatonin, this delivery method provides for a number of disadvantages, such as slow drug onset - it can take more than 30 minutes after administration for the blood plasma concentration of melatonin to reach its peak - and high required amounts of melatonin per dose (of up to 5 mg). In contrast, when delivered to the lungs via inhalation, the inventors propose that melatonin will have a much faster onset and will demonstrate much better bioavailability. Because of that, the dose can be up to 20-fold reduced (in comparison to known products) while achieving the desired benefits.
  • an inhalable formulation comprising melatonin can be uniquely tailored for delivery via a metered dose inhaler (MDI) to a subject’s lungs to treat a disease, disorder or condition responsive to melatonin.
  • MDI metered dose inhaler
  • a simple formulation of melatonin, an alcohol and a propellant provides for a chemically stable composition (such as one in which the active(s) resist degradation for an extended commercially relevant period for storage and use), with useful particle size distribution characteristics and without the need for further excipients.
  • the inhalable formulations described herein have demonstrated highly favourable fine particle fraction (FPF) and fine particle dose (FPD) thereby indicating that a relatively high proportion of the inhalable formulation, and entrained melatonin, is not just delivered but is delivered with an FPF indicating significant delivery to the subject’s lungs rather than deposition in the oropharynx.
  • FPF fine particle fraction
  • FPD fine particle dose
  • FPFs for commercially available liquid inhalable formulations such as Clenil
  • the inhalable formulations described herein are significantly higher even at greater dosing levels.
  • melatonin or combined melatonin and one or more cannabinoids approaches significant concentrations such as 1-2% w/w (this value being the combined level of non-volatile in the solution) a useful FPF and FPD profile may be maintained.
  • the use of an alcohol, such as ethanol surprisingly may be sufficient, even at the low relative amounts used, to maintain the levels of non-volatile in solution and avoid blockage of the MDI which would otherwise present significant challenges.
  • melatonin, and optionally one or more cannabinoids via an MDI approach with the observed efficiency allows the dosing of active to be kept advantageously low compared with prior art approaches and so the likelihood of the subject detecting an unpleasant taste from the melatonin, and optionally one or more cannabinoids, is advantageously reduced.
  • melatonin, and optionally one or more cannabinoids at higher levels can induce a cough reflex because of the irritation caused to the subject’s throat.
  • the formulations described herein allow for this to be avoided or minimised based on the low levels of melatonin, and optionally one or more cannabinoids, required to be formulated due to the efficiency of delivery.
  • the disclosure resides in an inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the melatonin is present at between about 0.01% w/w and about 0.5% w/w, or between about 0.015% w/w and about 0.5% w/w, or at between about 0.02% w/w and about 0.5% w/w, or at between about 0.025% w/w and about 0.5% w/w, or at between about 0.03% w/w and about 0.5% w/w, or at between about 0.035% w/w and about 0.5% w/w, or at between about 0.04% w/w and about 0.5% w/w, or at between about 0.045% w/w and about 0.5% w/w, or at between about 0.05% w/w and about 0.5% w/w, or at between about 0.055% w/w and about 0.5% w/w, or at between about 0.06% w/w and about 0.5% w/w, or at between about 0.065% w/w and about 0.5% w
  • the melatonin may be present at between about 0.01% w/w and about 0.4% w/w, or between about 0.015% w/w and about 0.4% w/w, or at between about 0.02% w/w and about 0.4% w/w, or at between about 0.025% w/w and about 0.4% w/w, or at between about 0.03% w/w and about 0.4% w/w, or at between about 0.035% w/w and about 0.4% w/w, or at between about 0.04% w/w and about 0.4% w/w, or at between about 0.045% w/w and about 0.4% w/w, or at between about 0.05% w/w and about 0.4% w/w, or at between about 0.055% w/w and about 0.4% w/w, or at between about 0.06% w/w and about 0.4% w/w, or at between about 0.065% w/w and about 0.4% w/w, or at between about 0.065%
  • the melatonin may be present at between about 0.01% w/w and about 0.3% w/w, or between about 0.015% w/w and about 0.3% w/w, or at between about 0.02% w/w and about 0.3% w/w, or at between about 0.025% w/w and about 0.3% w/w, or at between about 0.03% w/w and about 0.3% w/w, or at between about 0.035% w/w and about 0.3% w/w, or at between about 0.04% w/w and about 0.3% w/w, or at between about 0.045% w/w and about 0.3% w/w, or at between about 0.05% w/w and about 0.3% w/w, or at between about 0.055% w/w and about 0.3% w/w, or at between about 0.06% w/w and about 0.3% w/w, or at between about 0.065% w/w and about 0.3%
  • the melatonin may be present at between about 0.01% w/w and about 0.15% w/w, or between about 0.015% w/w and about 0.15% w/w, or at between about 0.02% w/w and about 0.15% w/w, or at between about 0.025% w/w and about 0.15% w/w, or at between about 0.03% w/w and about 0.15% w/w, or at between about 0.035% w/w and about 0.15% w/w, or at between about 0.04% w/w and about 0.15% w/w, or at between about 0.045% w/w and about 0.15% w/w, or at between about 0.05% w/w and about 0.15% w/w, or at between about 0.055% w/w and about 0.15% w/w, or at between about 0.06% w/w and about 0.15% w/w, or at between about 0.06% w/w and about 0.15%
  • an advantage of the present inhalable formulation is that much smaller amount of melatonin is needed to achieve the desired effects. While known products contain up to 5 mg of melatonin per dose, the present formulation may comprise as little as 25 pg or 50 pg of melatonin per 50 pL dose or 50 pg of melatonin per 63 pL dose, as demonstrated in the Examples.
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 250 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 250 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 250 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 250 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 250 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 250 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 250 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 200 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 200 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 200 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 200 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 200 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 200 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 200 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 150 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 150 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 150 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 150 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 150 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 150 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 150 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 100 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 100 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 100 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 100 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 100 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 100 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 100 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 90 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 90 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 90 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 90 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 90 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 90 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 90 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 80 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 80 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 80 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 80 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 80 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 80 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 80 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 75 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 75 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 75 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 75 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 75 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 75 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 75 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 70 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 70 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 70 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 70 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 70 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 70 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 70 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the melatonin may be present at between about 5 pg/50 pL w/v and about 65 pg/50 pL w/v, or at between about 7 pg/50 pL w/v and about 65 pg/50 pL w/v, or at between about 10 pg/50 pL w/v and about 65 pg/50 pL w/v, or at between about 12 pg/50 pL w/v and about 65 pg/50 pL w/v, or at between about 15 pg/50 pL w/v and about 65 pg/50 pL w/v, or at between about 17 pg/50 pL w/v and about 65 pg/50 pL w/v, or at between about 20 pg/50 pL w/v and about 65 pg/50 pL w/v, or at between about 20 pg/50 pL w
  • the dosing volume may be any volume between about 25 to about 100 pL, optionally the dosing volume may be 25 pL, 61 pL, 63 pL and 100 pL.
  • the person of skill in the art would know how to choose a suitable dosing volume for a particular application and based on body mass of the intended subject and the like.
  • the unit dose of melatonin will be determined by the end application.
  • a dose of approximately 10 pg to 40 pg may be sufficient when appropriately delivered.
  • the required dose may be between about 30 pg to 70 pg.
  • the choice of the right propellant is essential to achieve an inhalable formulation with the desired properties.
  • the propellant /ra//.s- l ,3,3,3-tetratluoroprop- l - ene (HFO-1234ze) is a hydrofluoroolefm (HFO). It is used as an environmentally friendly alternative to traditional hydrofluoroalkane (HF A) propellants, such as HFA- 134a (1,1,1,2-tetrafhioroethane) and HFA-227ea (1,1,1,2,3,3,3-heptafhioropropane).
  • HF A hydrofluoroalkane
  • HFA-134a and HFA-227ea have been commonly used as propellants in various applications such as air conditioning, refrigeration, and aerosols. However, despite their widespread use, they have several disadvantages, primarily related to their environmental impact and safety concerns. Both HFA-134a and HFA- 227ea have significant Global Warming Potentials (GWP), -1300 and -3350, respectively, thereby contributing to climate change by trapping heat in the atmosphere. Although they do not deplete the ozone layer, their high GWP means they are still potent greenhouse gases. Because of that, they are slowly being phased out and replaced by other, more sustainable propellants.
  • GWP Global Warming Potentials
  • HFO-1234ze has desirable properties, such as a very low Global Warming Potential (GWP) of around 1, making it an attractive alternative to higher-GWP substances. Due to its low toxicity, it is safe to be used in personal care products and pharmaceuticals.
  • GWP Global Warming Potential
  • HFA-152a (1,1- difluoroethane). While HFA-152a has a lower GWP than HFA-134a and HFA-227ea (approximately 138 compared to around 1300 and 3350, respectively), it still has a significantly higher GWP than HFO-1234ze, with a difference of two orders of magnitude. Consequently, HFO-1234ze may be a much more environmentally friendly option. Additionally, HFO-1234ze exhibits significantly reduced flammability under standard test conditions compared to HF Al 52a, making it safer to handle and store. In contrast, HFA-152a is flammable, necessitating additional safety measures during manufacturing. Therefore, HFO-1234ze may be a much better choice in terms of environmental impact, manufacturing and storage cost, and safety.
  • HFO-1234ze demonstrates these desirable properties in regard to environmental concerns and toxicity and may be an attractive alternative
  • HFO-1234ze is structurally very different to the traditionally known hydrofluorocarbons HFA-134a and HFA-227ea and, because of that, a person of skill in the art would expect it to behave quite differently in formulations.
  • HFO-1234ze is an olefin (an unsaturated fluorocarbon) and has therefore different chemical properties than the commonly used saturated alkane propellants.
  • HFOs may have a different solubility profile than HF As due to them being less polar than HF As.
  • the propellant may be present at an amount of at least 50% w/w, 55% w/w, 60% w/w, 65% w/w, 70% w/w, 75% w/w, 80% w/w, or 85% w/w, or 90% w/w, or 95% w/w of the entire formulation.
  • the Ci to Ce alcohol may be present at between l%-20% w/w, or between 1%-19% w/w, or between 1%-18% w/w, or between 1%-17% w/w, or between 1%- 16% w/w, or between 1%- 15% w/w, or between 1%- 14% w/w, or between 1%-13% w/w, or between 1%-12% w/w, or between 1%-11% w/w, or between l%-10% w/w, or between 2%-20% w/w, or between 2%-19% w/w, or between 2%-l 8% w/w, or between 2%-17% w/w, or between 2%-16% w/w, or between 2%- 15% w/w, or between 2%-14% w/w, or between 2%- 13% w/w, or between 2%-12% w/w, or between 2%-l 1% w/w/w
  • the Ci to Ce alcohol may be present at less than 10% w/w, or 9% w/w, or 8% w/w, or 7% w/w, or 6% w/w, or 5% w/w of the formulation. In a preferred embodiment, the Ci to Ce alcohol may be present at about 5% w/w of the formulation.
  • the Ci to Ce alcohol may be selected from a Ci to C4 alcohol, a C2 to C4 alcohol, and a C2 or C3 alcohol.
  • the Ci to Ce alcohol may be ethanol. In an even more preferred embodiment, the Ci to Ce alcohol may be ethanol and may be present at about 5% w/w of the formulation.
  • the inhalable formulation may be an inhalable solution.
  • the melatonin may be the only non-volatile component of the inhalable formulation or may be the only biologically active agent (in terms of treatment of sleep-related disorders) in the inhalable formulation or may be the only component of the formulation which is a solid (when not dissolved or otherwise in any formulation or mixture) at room temperature.
  • melatonin may be beneficial to co-administer melatonin with a cannabinoid.
  • This may be especially useful when the sleep disorder is related to a mental health disorder, such as anxiety, depression, a mood disorder, psychosis and other related conditions.
  • a mental health disorder such as anxiety, depression, a mood disorder, psychosis and other related conditions.
  • one or more cannabinoids can be formulated with melatonin and still provide for a desired FPF and FPD profile. Due to the solution-based formulation this means that when the formulation is delivered to a subject’s lungs each particle comprises similar levels of melatonin and cannabinoid allowing for a synergistic effect on delivery.
  • the inhalable formulation may comprise one or more cannabinoids.
  • the one or more cannabinoids may be selected from the group consisting of anandamide, 2-arachidonoylglycerol, cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichormevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabielsoin (CBE), cannabicyclol (CBL), cannabinodiol (CBND), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabitriol (CBT), delta-8-tetrahydrocann
  • CBC cannabi
  • the cannabinoids that contain stereochemistry may refer to a single pure enantiomer or racemic mixtures (containing 1 : 1 proportions of the R- and 5-enanti omers), or mixtures of any ratio of the enantiomers.
  • dronabinol is the generic name for a synthetic delta-9-tetrahydrocannabinol.
  • dronabinol and delta-9-tetrahydrocannabinol are two accepted terms for the same active pharmaceutical ingredient. That is, the terms may be used interchangeably herein.
  • the one or more cannabinoids may be cannabidiol (CBD) or dronabinol.
  • the one or more cannabinoids may be cannabidiol (CBD) and dronabinol.
  • the one or more cannabinoids may be present in a total amount at between about 0.1% w/w and about 4.0% w/w, or at between about 0.15% w/w and about 4.0% w/w, or at between about 0.2% w/w and about 4.0% w/w, or at between about 0.25% w/w and about 4.0% w/w, or at between about 0.3% w/w and about 4.0% w/w, or at between about 0.35% w/w and about 3.5% w/w, or at between about 0.4% w/w and about 3.5% w/w, or between about 0.1% w/w and about 3.5% w/w, or at between about 0.15% w/w and about 3.5% w/w, or at between about 0.2% w/w and about 3.5% w/w, or at between about 0.25% w/w and about 3.5% w/w, or at between about 0.3% w/w and about 3.5% w/w/w, or at between about
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/ 50 pL w/v and about 2000 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 2000 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 2000 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 2000 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 2000 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 2000 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 2000 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 1500 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 1500 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 1000 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 1000 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 1000 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 1000 pg/50 pL w/v, or atbetween about 90 pg/50 pL w/v and about 1000 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 1000 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 1000 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 900 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 900 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 900 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 900 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 900 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 900 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 900 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 800 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 800 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 800 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 800 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 800 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 800 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 800 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 700 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 700 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 700 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 700 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 700 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 700 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 700 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 600 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 600 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 600 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 600 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 600 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 600 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 600 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 500 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 500 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 500 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 500 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 500 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 500 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 500 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 400 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 400 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 400 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 400 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 400 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 400 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 400 pg/50 pL w/v,
  • the one or more cannabinoids may be present in a total amount at between about 50 pg/50 pL w/v and about 350 pg/50 pL w/v, or at between about 60 pg/50 pL w/v and about 350 pg/50 pL w/v, or at between about 70 pg/50 pL w/v and about 350 pg/50 pL w/v, or at between about 80 pg/50 pL w/v and about 350 pg/50 pL w/v, or at between about 90 pg/50 pL w/v and about 350 pg/50 pL w/v, or at between about 100 pg/50 pL w/v and about 350 pg/50 pL w/v, or at between about 110 pg/50 pL w/v and about 350 pg/50 pL w/v,
  • the particle size distribution in the inhalable formulation plays an important role to achieve the desired delivery to the deep lungs.
  • the components of the formulation and their percentage ranges have been carefully chosen to achieve the necessary particle size distribution when delivered.
  • the inhalable formulation may provide for a fine particle fraction of greater than 40%, or greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%.
  • the inhalable formulation may comprise, consist of or consist essentially of: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); and, optionally, one or more cannabinoids, optionally one of dronabinol and/or cannabidiol (CBD).
  • melatonin a Ci to Ce alcohol
  • a propellent which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze)
  • cannabinoids optionally one of dronabinol and/or cannabidiol (CBD).
  • the inhalable formulation may comprise, consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the inhalable formulation may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; one or more cannabinoids, optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the inhalable formulation may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; cannabidiol (CBD), optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the inhalable formulation may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; dronabinol, optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the inhalable formulation may consist of or consist essentially of : melatonin, optionally present at between about 0.025% w/w and about 0.1% w/w of the formulation; a Ci to Ce alcohol, optionally ethanol, optionally present at between about 2% and about 20% w/w of the formulation; dronabinol and cannabidiol (CBD), optionally present at a combined amount of between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • the total mass of melatonin and any one or more cannabinoids per 50 pL metered dose of the formulation may be less than 1 mg, or less than 950 pg, or less than 900 pg, or less than 850 pg, or less than 700 pg, or less than 650 pg, or less than 600 pg, or less than 550 pg, or less than 500 pg, or less than 450 pg.
  • a metered dose inhaler comprising an inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze).
  • MDIs Metered dose inhalers
  • respiratory diseases among other conditions
  • MDIs are used to treat respiratory diseases, among other conditions, by delivering a reliable, consistent dose of a pharmaceutical to the patients’ airways through inhalation. They do not rely on heating and are safe and convenient for users to carry and draw an inhalation breath from when in use.
  • MDIs present challenges in terms of suitable formulations which will be chemically stable and will generate appropriate particle sizes containing the active agent. Since they do not rely on heating, and produce almost instantaneous evaporation of multiple formulation components, it is necessary to achieve a thermodynamic balance of the formulation components to ensure the active agent is appropriately maintained within the droplets so that the active agent can be delivered to the lungs.
  • Formulation is also key to ensuring the active agent is not lost or separates out during storage.
  • the formulation must also be capable of relatively long-term storage without significant deterioration of the formulation and, in at least some instances, be such that in being dispensed from an MDI the active is restrained from separating from other components of the formulation and depositing in the oral cavity or pharynx which may result in a limited therapeutic response.
  • This requires control of a highly dynamic system of formulation components which are expanding, following release from the MDI, and rapidly cooling and condensing. Careful balance of the relative solubilities of the components is crucial along with achieving particles having an appropriate average particle or droplet diameter to provide desirable delivery to the deep lungs.
  • Metered dose inhalers are well-known in the art and a wide range of such MDIs may be selected for use with the formulation of the first aspect. Such MDIs are familiar to the person of skill in the art and may be selected from those which are commercially available.
  • the MDIs which are available all have a canister which can be attached to the MDI or which may be built into it and which can contain the active agent being delivered.
  • Such canisters are adapted to contain a pressurised fluid and often are designed for containing hydrofluorocarbon-type propellant formulations.
  • valve of the canister that is used to store the formulation controls the release of the inhalable formulation from the canister. It is designed to release a precise amount of the inhalable formulation, to prevent leakage of the propellant or the API and to help regulate the aerosol mist.
  • the type of valve may therefore influence the accuracy of the dose and reliability of the delivery system.
  • the person of skill in the art would know how to select a suitable valve.
  • the valve may be an Aptar valve.
  • the valve may be an Aptar DF316 (DF30PLUS)/63 RCU PRE7R or an Aptar ZEN316 PRE7R valve.
  • the valve may be an Aptar ZEN316 PRE7R valve.
  • a gasket is commonly used as a sealing component that ensures that the valve fits securely within the canister and prevents any unwanted leakage of the contents.
  • the gasket is placed between the valve and the canister. Gaskets have lower leakage rates which are generally much higher with low GWP propellant formulations (such as HFO- 1234 ze) when compared to traditional propellants.
  • a Cyclo-olefin copolymer (COC) gasket reduces Oxygen and water uptake rates when compared to traditional gaskets.
  • the gasket may be a Cyclo-olefin copolymer (COC) gasket.
  • the diameter of the aperture of the MDI may influence the average particle size which is subsequently formed and so can have an influence on delivery.
  • the aperture of the MDI may have a diameter of between 0.10 mm and 0.50 mm, or between 0.15 mm and 0.40 mm or between 0.20 mm and 0.30 mm. [0131] In an embodiment, the aperture has a diameter of about 0.23 mm.
  • the metered dose inhaler may comprise an inhalable formulation comprising: melatonin; a Ci to Ce alcohol; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein the metered dose inhaler comprises an Aptar valve, preferably an Aptar ZEN316 PRE7R valve, and, optionally, a COC gasket.
  • a metered dose inhaler typically is a pre-metered multidose inhaler.
  • the canister of the metered dose inhaler may comprise up to 200 doses, or up to 190 doses, or up to 180 doses, or up to 170 doses, or up to 160 doses of the inhalable formulation.
  • the dosing volume may be any volume between about 25 pL to about 100 pL, optionally the dosing volume may be 25 pL, 61 pL, 63 pL and 100 pL.
  • the inhalable formulation may be as defined in any one or more embodiments of the first aspect.
  • the disclosure resides in a method of delivering melatonin to a subject including the steps of: providing the inhalable formulation of the first aspect; and allowing the subject to inhale the inhalable formulation, to thereby deliver the melatonin to the subject.
  • the inhalable formulation of the first aspect may be delivered to the subject by activation of a metered dose inhaler, preferably the metered dose inhaler of the second aspect.
  • the inhalable formulation of the first aspect may be delivered to the lungs of the subj ect by the subj ect’ s inhalation of the dose emitted (the emitted dose) from the MDI of the second aspect.
  • Fine particle fraction is defined in general terms as the fraction or percentage of the drug mass contained in an aerosol cloud that may be small enough to enter the lungs and exert a clinical effect. In general, an aerodynamic diameter of 5 pm is considered to be the approximate border between "fine” and “coarse” particles. Unless stated otherwise, fine particle fraction (FPF) herein refers to the percentage of the drug mass contained in an aerosol cloud having an aerodynamic diameter of below 5 pm. For example, if it is stated that the fine particle fraction is greater than 40% then at least 40% of the inhalable formulation forms particles with an aerodynamic diameter of below 5 pm when aerosolised. A person of skill in the art will be aware of standard approaches and analytical tools by which to measure the fine particle fraction of an inhalable solution.
  • the PSA could, for example, use a next generation cascade impactor (NGI).
  • NKI next generation cascade impactor
  • the FPF described herein have been determined using a next generation cascade impactor (NGI).
  • NTI next generation cascade impactor
  • the inhalable formulation may be delivered as an emitted dose having a fine particle fraction of greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%.
  • the inhalable formulation is delivered having a fine particle fraction of about 40%, about 45%, about 50%, about 55%, about 60%, or about 65%, or about 70%, or about 75%, or about 80%.
  • Fine particle dose refers to the mass of particles that have an aerodynamic diameter of below 5 pm within the total emitted dose.
  • FPD Fine particle dose
  • the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 10 pg and about 35 pg, or of between about 11 pg and about 35 pg, or of between about 12 pg and about 35 pg, or of between about 13 pg and about 35 pg, or of between about 14 pg and about 35 pg, or of between about 15 pg and about 35 pg, or of between about 10 pg and about 34 pg, or of between about 11 pg and about 34 pg, or of between about 12 pg and about 34 pg, or of between about 13 pg and about 34 pg, or of between about 14 pg and about 34 pg, or of between about 15 pg and about 34 pg, or of between about 10 pg and about 33 pg, or of between about 11 pg and about 33 pg, or of between about 12 pg
  • the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 17 pg and about 35 pg, or of between about 18 pg and about 35 pg, or of between about 19 pg and about 35 pg, or of between about 20 pg and about 35 pg, or of between about 21 pg and about 35 pg, or of between about 17 pg and about 34 pg, or of between about 18 pg and about 34 pg, or of between about 19 pg and about 34 pg, or of between about 20 pg and about 34 pg, or of between about 21 pg and about 34 pg, or of between about 17 pg and about 33 pg, or of between about 18 pg and about 33 pg, or of between about 19 pg and about 33 pg, or of between about 20 pg and about 33 pg, or of between about 21 pg, or about 21 pg, or about 33
  • the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 15 pg and about 40 pg, or of between about 16 pg and about 40 pg, or of between about 17 pg and about 40 pg, or of between about 18 pg and about 40 pg, or of between about 19 pg and about 40 pg, or of between about 20 pg and about 40 pg, or of between about 15 pg and about 39 pg, or of between about 16 pg and about 39 pg, or of between about 17 pg and about 39 pg, or of between about 18 pg and about 39 pig, or of between about 19 pig and about 39 pig, or of between about 20 pig and about 39 pig, between about 15 pig and about 38 pig, or of between about 16 pig and about 38 pig, or of between about 17 pig and about 38 pig, or of between about 18 pig, or of between about 18 pig, or
  • the inhalable formulation may be delivered as an emitted dose having a fine particle dose of melatonin of between about 21 pg and about 40 pg, or of between about 22 pg and about 40 pg, or of between about 23 pg and about 40 pg, or of between about 24 pg and about 40 pg, or of between about 25 pg and about 40 pg, or of between about 21 pg and about 39 pg, or of between about 22 pg and about 39 pg, or of between about 23 pg and about 39 pg, or of between about 24 pg and about 39 pg, or of between about 25 pg and about 39 pg, between about 21 pg and about 38 pg, or of between about 22 pg and about 38 pg, or of between about 23 pg and about 38 pg, or of between about 24 pg and about 38 pg, or of between about 25 pg and about 39 pg, between about 21 pg
  • the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; and a propellent, which is /ra/z.s- l ,3,3,3-tetrafluoroprop- l -ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and/or an FPD of between about 10 pg and about 35 pg from a 50 pg/50 pL metered dose, optionally an FPD of between about 13 pg and about 32 pg, or of between about 15 pg and about 30 pg, or of between about 17 pg and about 30 pg, or of between about 20 pg and about 30 pg, from a 50 pg/50 pL metered dose,
  • the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; and a propellent, which is /ra/z.s- l ,3,3,3-tetrafluoroprop- l -ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and/or an FPD of between about 10 pg and about 35 pg from a 25 pg/50 pL metered dose, optionally an FPD of between about 11 pg and about 25 pg, or of between about 12 pg and about 20 pg, or of between about 13 pg and about 20 pg, or of between about 15 pg and about 20 pg, from a 25 pg/50 pL metered dose,
  • the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; and a propellent, which is lrans- ⁇ ,3,3,3-tetrafluoroprop-l -ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and/or an FPD of between about 15 pg and about 40 pg from a 50 pg/63 pL metered dose, optionally an FPD of between about 17 pg and about 39 pg, or of between about 20 pg and about 38 pg, or of between about 22 pg and about 37 pg, or of between about 25 pg and about 35 pg, from a 50 pg/63
  • the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; one or more cannabinoids, optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and/or an FPD of between about 10 pg and about 35 pg from a 50 pg/50 pL metered dose, optionally an FPD of between about 13 pg and about 32 pg, or of between about 15 pg and about 30 pg, or of between about 17 pg and about
  • the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; one or more cannabinoids, optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and/or an FPD of between about 15 pg and about 40 pg from a 50 pg/63 pL metered dose, optionally an FPD of between about 17 pg and about 39 pg, or of between about 20 pg and about 38 pg, or of between about 22 pg and about
  • the inhalable formulation may comprise melatonin; a Ci to Ce alcohol, optionally ethanol; one or more cannabinoids, optionally present at between about 0.2% w/w and about 0.8% w/w of the formulation; and and a propellent, which is traw -l,3,3,3-tetrafluoroprop-l-ene (HFO 1234ze); wherein, an emitted dose distribution as follows is provided: an FPF of greater than 40%, optionally greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%; and/or an FPD of between about 10 pg and about 35 pg from a 25 pg/50 pL metered dose, optionally an FPD of between about 11 pg and about 25 pg, or of between about 12 pg and about 20 pg, or of between about 13 pg and
  • the metered dose inhaler may be as described in any one of the embodiments of the second aspect.
  • the disclosure resides in a method of treating a disease, disorder or condition in a subject, comprising administering an effective amount of the inhalable formulation of the first aspect.
  • the disclosure resides in a use of the inhalable formulation of the first aspect in the manufacture of a medicament for the treatment of a disease, disorder or condition.
  • the disclosure resides in a use of the inhalable formulation of the first aspect for the treatment of a disease, disorder or condition.
  • the disclosure resides in the inhalable formulation of the first aspect for use in the treatment of a disease, disorder or condition responsive to melatonin.
  • the disease, disorder or condition may be a sleep disorder.
  • the sleep disorder may involve difficulty falling asleep, remaining asleep, or excessive sleepiness.
  • treating a subject with a sleep disorder means modifying or improving the sleep-wake cycle.
  • treating a sleep disorder or modifying or improving the sleepwake cycle in a subject may include improving sleep sensation determined by subjective judgment using psychological evaluation techniques or improving the sleep state determined objectively using techniques of estimating sleep and wakefulness states based on continuous recording of activity amounts.
  • the obstructive sleep apnoea questionnaire can be used to examine the sleep sensation of the previous night to the present morning upon arising. The questionnaire is based on the five factors of sleepiness upon arising, sleep initiation and sleep maintenance, dream quality, recovery from fatigue, and elongation of sleep length and has been verified in regard to the reliability and validity of the respective factors.
  • the sleep disorder may be a dyssomnia.
  • Dyssomnia can include psychophysiological insomnia, sleep state misperception, idiopathic insomnia, obstructive sleep apnoea syndrome, central sleep apnoea syndrome, central alveolar hypoventilation syndrome, periodic limb movement disorder, restless leg syndrome, inadequate sleep hygiene, environmental sleep disorder, altitude insomnia, adjustment sleep disorder, insufficient sleep syndrome, limit-setting sleep disorder, sleep-onset association disorder, nocturnal eating or drinking syndrome, hypnotic dependent sleep disorder, stimulant-dependent sleep disorder, alcohol-dependent sleep disorder, toxin- induced sleep disorder, time zone change (jet lag) syndrome, shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome and non-24-hour sleep-wake disorder.
  • the sleep disorder may be a parasomnia.
  • Parasomnia can include confusional arousals, sleepwalking and sleep terrors, rhythmic movement disorder, sleep starts, sleep talking and nocturnal leg cramps.
  • the sleep disorder may be associated with a medical or psychiatric disorder.
  • the medical or psychiatric disorder can include psychoses, mood disorders, anxiety disorders, panic disorders, alcoholism, cerebral degenerative disorders, dementia, parkinsonism, fatal familial insomnia, sleep-related epilepsy, electrical status epilepticus of sleep, sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia, chronic obstructive pulmonary disease, sleep-related asthma, sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositis syndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia and post-surgical sleep disorder.
  • the treatment can include administering one dose or two or more doses of the formulations of the first aspect.
  • the treatment may be administered before bedtime, preferably within 2 hours, or 1.5 hours, or 1 hour, or 30 minutes, or 20 minutes, or 15 minutes, or 10 minutes before bedtime.
  • Example 1 Preparation of melatonin formulations (50 pL dose)
  • Formulations 1 and 3 contain 25 pg/50 pL of melatonin and formulations 2 and 4 contain 50 pg/50 pL of melatonin.
  • Table 1 Melatonin formulations with HFA134a and HFO1234ze as propellants.
  • Example 2 Drug Delivery Metrics (50 pL dose)
  • Drug Delivery Metrics were determined by Next Generation Cascade Impactor (NGI) at 301/min sampling flow rate as described in United States Pharmacopoeia ⁇ 601> Apparatus 6 for Metered-Dose Inhalers (see table 2 and FIGs 1 and 2).
  • NTI Next Generation Cascade Impactor
  • the metered doses in pg, the delivered doses in pg, and fine particle doses in pg and fine particle fractions in % based on the delivered doses were determined for the four prepared melatonin formulations.
  • Example 3 Stability testing (50 pL dose)
  • the cans were removed from stability cabinets at the given timepoints.
  • the MDIs were chilled, opened and the formulations were collected into volumetric flasks after brief storage below the propellant boiling point.
  • the MDI was washed out and made to volume using diluent.
  • the solution concentration was quantitatively determined via a HPLC-UV method derived from USP Melatonin monograph.
  • the column used was a C18 150x4.6mm 5pm and the mobile phase was potassium phosphate buffer and acetonitrile.
  • Formulations 5 and 6 contain 50 pg/50 pL of melatonin and formulations 7 and 8 contain 25 pg/50 pL of melatonin (see table 4).
  • the can closure system & actuator canister includes a 19 mL aluminium plasma treated canister (Presspart), a 50 pL metering valve and a Presspart NM200 actuator with 0.23 mm orifice diameter.
  • Formulations 9 and 10 contain 50 pg/63 pL of melatonin and formulations 11 and 12 contain 25 pg/63 pL of melatonin (see table 5).
  • the can closure system & actuator canister includes a 19 mL aluminium plasma treated canister (Presspart), a 63 pL metering valve and a Presspart NM200 actuator with 0.23 mm orifice diameter.
  • Formulations 5 to 8 contain 300 pg/50 pL of CBD and formulations 9 to 12 contain 300 pg/63 pL of CBD. All formulations comprise HFO1234ze as propellant.
  • Table 4 Melatonin formulations with CBD (50pl Metered Dose).
  • Table 5 Melatonin formulation with CBD (63 pl Metered Dose).
  • Example 5 Drug Delivery Metrics of formulations comprising melatonin with CBD [0181] Drug Delivery Metrics were determined by Next Generation Cascade Impactor (NGI) at 301/min sampling flow rate as described in United States Pharmacopoeia ⁇ 601> Apparatus 6 for Metered-Dose Inhalers (see table 6 and 7). The metered doses in pg, the delivered doses in pg, and fine particle doses in pg and fine particle fractions in % based on the delivered doses were determined for the four prepared melatonin + CBD formulations.
  • NTI Next Generation Cascade Impactor
  • Table 6 Drug Delivery Metrics for formulations 5 to 8.
  • Example 6 Melatonin formulations (63 pL dose)
  • Formulation 13 with 50 pg per 63 L melatonin, 5% w/w ethanol, and HFO1234ze as propellant was prepared (Table 8) according to the following procedure.
  • Melatonin was added by mass to a conical flask. The mass of ethanol was added to the same conical flask. The conical flask was ultrasonicated for 10 mins to form a clear solution. The bulk formulation mass (less propellant) was added ( ⁇ 2%) to a C128 plasma treated aluminium canister (Presspart, UK). An Aptar 63pl valve was placed and crimped to the canister using a Pamasol P2002 pneumatic crimper.
  • the propellant was filled by mass ( ⁇ 2%) through the valve using a Pamasol P2011/10 pneumatic propellant filler.
  • the mass of each canister-valve assembly was recorded, before and after bulk addition, and after propellant mass addition.
  • the formulation was also filled in glass bottles to allow visual assessment of the final formulation (see FIG. 3). A clear solution was observed at manufacture and after four weeks at 5°C.
  • the melatonin can content observed in MDIs following storage for 0, 3 and 6- months at 40°C/75%RH is presented in Table 10. Percentage relative to the target melatonin content (6893pg) is presented (initial time point range was 98-100%, see
  • Table 11 Melatonin Delivered Dose and Metered Dose Through Can-Use Life
  • Table 12 Melatonin Delivered Dose and Metered Dose Through Can-Use Life
  • Table 13 Melatonin Delivered Dose and Metered Dose Through Can-Use Life
  • Table 14 presents the drug delivery metrics for MDIs stored for up to 6-months at 40°C/75%RH; as determined by NGI at a sampling flow rate of 301/min.
  • canister priming all canisters were within expectation after one dose had been fired (see FIG. 11). Thus, a single priming dose (dose number 1) is sufficient to prime all metering valves to within 25% of target shot weight.
  • Table 15 Shot weights (mean ⁇ standard deviation) at 0, 3, and 6 months.

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Abstract

La présente divulgation concerne une formulation inhalable contenant de la mélatonine et, éventuellement, un cannabinoïde. En outre, la présente divulgation concerne un inhalateur doseur contenant la formulation inhalable, ainsi que des procédés et des utilisations de la formulation inhalable.
PCT/AU2024/051244 2023-11-23 2024-11-22 Formulation inhalable Pending WO2025107035A1 (fr)

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Citations (3)

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WO2021046919A1 (fr) * 2019-09-12 2021-03-18 深圳雾芯科技有限公司 Liquide à vapoter
US20210260031A1 (en) * 2020-02-25 2021-08-26 North Cell Pharmaceuticals Inc. Formulations for reducing anxiety in non-human mammals by increasing brain serotonin levels

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WO2010074753A1 (fr) * 2008-12-23 2010-07-01 Map Pharmaceuticals, Inc. Dispositifs d'inhalation et procédés associés pour administration de composés hypnotiques sédatifs
WO2021046919A1 (fr) * 2019-09-12 2021-03-18 深圳雾芯科技有限公司 Liquide à vapoter
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GAIHA SHIVANI MATHUR, LIN CRYSTAL, LEMPERT LAUREN KASS, HALPERN-FELSHER BONNIE: "Use Patterns, Flavors, Brands, and Ingredients of Nonnicotine e-Cigarettes Among Adolescents, Young Adults, and Adults in the United States", JAMA NETWORK OPEN, JAMA NETWORK, vol. 5, no. 5, 2 May 2022 (2022-05-02), pages e2216194, XP093315610, ISSN: 2574-3805, DOI: 10.1001/jamanetworkopen.2022.16194 *
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MARASINI NIRMAL, KOMALLA VARSHA, RAO LINGZHE, DUKE DANIEL, HONNERY DAMON, STEIN STEPHEN W, MYATT BENJAMIN, COCKS PHIL, XIN ONG HUI: "Solution-based pressurized metered dose inhaler formulations using HFA134a, HFA152a and HFO1234ze(E) propellants: Analysis of size, aerosolization performance and particle morphology", 1 January 2022 (2022-01-01), XP093315607, Retrieved from the Internet <URL:https://ddl-conference.com/wp-content/uploads/2022/11/12.Marasini.pdf> *
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