AU2018210671A1

AU2018210671A1 - Inhaler device for inhalable liquids

Info

Publication number: AU2018210671A1
Application number: AU2018210671A
Authority: AU
Inventors: Scott Cameron COURTNEY
Original assignee: Medical Development International Ltd; Medical Developments International Ltd
Current assignee: Medical Developments International Ltd
Priority date: 2017-01-18
Filing date: 2018-01-17
Publication date: 2019-08-08
Also published as: WO2018132867A1; CN110300610A

Abstract

The application relates to a product for the storage and/or administration of inhalable volatile liquids such as halogenated volatile liquids, to a patient. The application also relates to a process for manufacturing the product and a method for the storage and/or administration of inhalable volatile liquids such as halogenated volatile liquids, to a patient.

Description

INHALER DEVICE FOR INHALABLE LIQUIDS

FIELD

BACKGROUND

The storage and administration of inhalable liquids to patients that comprise active agents, or that are themselves the active agent, commonly presents challenges. Due to patient preference and ease of self-administration or administration in a hospital setting or other settings as required, active agents such as therapeutic agents or pharmaceutical agents, are often formulated for oral delivery in the form of tablets and capsules, nasal delivery in the form of sprays and liquid formulations for intravenous delivery.

Where it is advantageous to administer active agents to a patient’s lungs, for example to treat or alleviate respiratory diseases, the active agent may be administered by the oral inhalation route, alone or in combination with the intranasal route. Suitable inhaler devices may include, for example, metered dose inhalers and dry powder inhalers. These types of oral inhalation devices typically require pressurised means to deliver the active agent to the desired site of action in the lungs. In addition, liquids that contain active agents or that are themselves the active agent usually require transformation into an inhalable, respirational, form at the point of administration to be suitable for delivery by the inhalation route. Transforming a liquid into an inhalable form, such as by nebulisation or aerosolizing into respirational sized droplets or heating to form a vapour, requires delivery devices to include moving, mechanical, heating and/or electrical means which adds to the complexity of the design, manufacturing and end user costs, operability and/or patient use.

The use of volatile liquids as active agents or comprising active agents is known. One such example is halogenated volatile liquids. Halogenated volatile liquids have been described as useful for inducing and/or maintaining anaesthesia (including amnesia, muscle paralysis, and/or sedation) and/or analgesia and may therefore be useful as anaesthetics and/or analgesics. The anaesthetic properties of fluorinated compounds have been known since at least 1946 (Robbins, B.H. J Pharmacol Exp Trier (1946) 86: 197-204). This was followed by the introduction of fluoroxene, halothane and methoxyflurane into clinical use in the 1950s and the subsequent development of enflurane, isoflurane, sevoflurane and desflurane which

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PCT/AU2018/050025 are in clinical use in some countries today (Terrell, R.C. Anesthesiology (2008) 108 (3): 5313).

Halogenated volatile liquids, when used for general anaesthesia, may be delivered to a patient under positive pressure via a delivery system that includes a vaporizer and a flow of breathable carrier gas. More recently, halogenated volatile liquids have been formulated for use in local or regional anaesthesia and delivery via non-inhalation routes. Examples include formulation as: microdroplets for intradermal or intravenous injection (e.g.

US4,725,442); aqueous solutions for intrathecal or epidural delivery (e.g. W02008/036858); swab, droplets, spray or aerosol for transmucosal delivery (e.g. WO2010/025505); aqueous based solutions comprising an extractive solvent in an amount effective to reduce the volatility, vaporisation or evaporation of the volatile anaesthetic for transdermal, topical, mucosal, buccal, rectal, vaginal, intramuscular, subcutaneous, perineural infiltration, intrathecal or epidural delivery (e.g. W02009/094460, W02009/094459); compositions suitable for formulation into a medical patch (e.g. WO2014/143964); compositions suitable for formulation as a solution, suspension, cream, paste, oil, lotion, gel, foam, hydrogel, ointment, liposome, emulsion, liquid crystal emulsion and nanoemulsions for topical, intrathecal, epidural, transdermal, topical, oral, intra-articular, mucosal, buccal, rectal, vaginal, intramuscular, intravesical and subcutaneous delivery (e.g. W02008/070490, W02009/094460, WO2010/129686); and stable and injectable liquid formulations (WO2013/016511).

The main consideration(s) for the safe storage and handling of volatile liquids commonly include vapour pressure build up, the robustness of the container and the integrity of the container seal(s). The chemical nature of the volatile liquid may also be important if the active agent is capable of permeating, solubilizing or otherwise reacting with the container material(s) upon storage. A number of storage containers for halogenated volatile liquids have been described including: rigid polymeric containers as a replacement for glass vials, such as capped bottles large tanks, shipping containers (e.g. W01999/034762, WO2012/116187); rigid polymeric bottles fitted with a gasketless valve assembly and pliable containers with a threaded spout for fluid connection to deliver liquid anaesthetics to an anaesthetic machine or vaporizer (e.g. WO2010/135436, WO2013/106608, WO2013/149263, WO2015/034978); a container with a capped membrane for delivering a stored liquid anaesthetic to a vaporizer via a slotted tube (W02009/117529); and rigid polymeric and aluminium containers optionally coated with materials to impart or enhance vapour barrier characteristics or container inertness (e.g. W02002/022195, W02003/032890, WO2010/129796).

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PCT/AU2018/050025

Despite the various advances in formulating volatile liquids in non-inhalable forms, such as the halogenated volatile liquids, as well as containers to store them, there still remains a need for inhalable forms of volatile liquids and devices to store and/or administer them to patients.

Attempts to design new inhalers for inhalable medicines in general are ongoing. For example, W02008/040062 describes a diverse number of inhaler device concepts that depend on complex constructions and moving parts for storing and/or delivering inhalable liquids and powdered solids into a user’s mouth or nose. The various devices described are adapted to hold one or two medicament containers in the form of pressurised canisters, ampoules, vials and plungers. The devices are described as being activated by sliding an outer wall of the device in relation to an inner wall of the device to deliver the liquid medication from a medication container. In a number of embodiments, the device includes a moveable mouthpiece which deploys in order to open the air pathway. The device is also described as including one or more one-way valves to provide a unidirectional air flow for one or both inhaled air and exhaled air (a series of one-way valves to direct the flow of inhaled and exhaled air has also been generally described in W02007/033400 which is an incorporation by reference of the device described in W01997/003711).

When required for use, the devices of W02008/040062 are claimed as being capable of releasing the medication by punching means namely two punches to perforate the two frangible ends respectively of a medication container having frangible ends, although various other means are generally described including: pressurised means (e.g. by a pressurised canister); frangible means (e.g. by rupturing an ampoule with a striker or by punching a frangible membrane or seal of a vial with punch means); crushable means (e.g. by crushing a vial with a plunger); dislodging means (e.g. by dislodging an unscrewed cap from a vial); and plunging means (e.g. by plunging the medication from the plunger barrel).

However, inhalable liquids such as halogenated volatile liquids require an effective air chamber into which the vapour may evaporate and allow an effective airflow through the air/vapour chamber for delivery to a patient. Accordingly, embodiments such as those described in, for example, Figures 48A, 48B, 48C, 49A, 49B, 50A, 50B, 51 A, 51B, 56A, 56B, 57, 58A, 58B, 58C and 58D of W02008/040062, would not be expected to work in practice as the evaporative means (or wick) is prevented from being effectively exposed to the released liquid by the walls of the liquid storage container itself.

The present invention provides a new product for the storage and administration of inhalable liquids as a vapour to a patient offering one or more advantages or improvements over known inhaler products, in particular known inhaler products for the storage and

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PCT/AU2018/050025 administration of halogenated volatile liquids such as methoxyflurane for use as an analgesic.

The product is capable of storing and administering an inhalable liquid, such as a halogenated volatile liquid, as a vapour by providing an inhaler device comprising a passive evaporation support material located within the inhaler device and pre-loaded with the liquid wherein the inhaler device is stored within a vapour impermeable sachet to sealingly store the inhalable liquid as it forms a partial vapour upon storage within the inhaler device.

The product is considered to offer one or more advantages, for example, an easy to use, pre-loaded (i.e. primed for use) for rapid administration, readily portable inhaler device for delivering an inhalable liquid (such as methoxyflurane) to a patient. Other advantages of the product may also include reductions in manufacturing costs, shipping, packaging, storage and disposal costs as well as material wastage, by avoiding the need to store the liquid in a separately manufactured container.

The product is considered to obviate the need for a separate packaging process and storage container for an inhalable liquid to be delivered to a patient via an inhaler device. The product is therefore considered to provide an advantage in particular for the storage and delivery of methoxyflurane which currently involves packaging and storage of the methoxyflurane as a liquid in a separate container (glass vial with screw-cap lid) prior to the administrator (e.g. paramedic) or user manually loading the liquid (by opening the glass vial and carefully pouring its contents i.e. the dosing amount) into the device (onto the wick) when the device is required to deliver the drug to the patient (for analgesia).

Accordingly, in contrast to the current commercial product and method of storing and administering methoxyflurane to a patient for analgesia, the product and method according to the present application allows for immediate availability of the required dosing amount of methoxyflurane to the patient once the vapour impermeable sachet is opened.

SUMMARY

According to a first aspect, there is provided a product for the storage and administration of a dosing amount of an inhalable liquid to a patient, said product comprising:

(1) an inhaler device;

(2) a passive evaporation support material located within the inhaler device and pre-loaded with the dosing amount of the liquid; and (3) a vapour impermeable sachet;

wherein the inhaler device is sealed within the vapour impermeable sachet and further wherein the vapour impermeable sachet is adapted to exclude or minimise excess air to

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PCT/AU2018/050025 sealingly store the dosing amount within the inhaler device as it forms a (partial) vapour upon storage of the product such that when the vapour impermeable sachet is opened, the dosing amount is available for administration to the patient as a vapour from the inhaler device.

According to a second aspect, there is provided a process for producing the product according to the first aspect comprising the steps of:

(1) providing an inhaler device comprising an external housing and an internally located passive evaporation support material;

(2) depositing a dosing amount of an inhalable liquid onto the passive evaporation support material to pre-load the liquid therein to allow for delivery of the inhalable liquid as a vapour to the patient when the inhaler device is in use;

(3) surrounding the inhaler device with a vapour impermeable material;

(4) excluding or minimising excess air intermediate the external housing and vapour impermeable material; and (5) sealing the vapour impermeable material to form a vapour impermeable sachet to sealingly store the dosing amount within the inhaler device;

wherein the excess air is excluded or minimised to sealingly store the dosing amount within the inhaler device as it forms a (partial) vapour upon storage of the product such that when the vapour impermeable sachet is opened, the dosing amount is available for administration to the patient as a vapour from the inhaler device.

It will be understood that the process of excluding or minimising the excess air in step (4) and sealing the vapour impermeable material in step (5) may, in practice, occur simultaneously or in reverse order, that is, the exclusion or minimisation of excess air may occur prior to, following or during the process of sealing.

The vapour impermeable material for use in the process according to the second aspect may be a vapour impermeable film or foil and may, prior to sealing to enclose the device comprising the pre-loaded inhalable liquid within the vapour impermeable sachet for storage, be provided in the form of for example: (a) a sachet with an opening to allow for insertion of the inhaler thereinto prior to sealing the device within the material (i.e. in the form of the vapour impermeable sachet); or (b) one or more (for example, two (2)) sheets to surround the inhaler or to place the inhaler there-between i.e. from which the vapour impermeable sachet is formed upon sealing).

According to a third aspect, there is provided a method for the storage and administration of a dosing amount of an inhalable liquid to a patient, said method comprising:

WO 2018/132867

PCT/AU2018/050025 (1) sealingly storing an inhaler device within a vapour impermeable sachet wherein the inhaler device comprises a passive evaporation support material that is located internally within an external housing of the device and is pre-loaded with the dosing amount of the liquid;

(2) opening the vapour impermeable sachet to access the inhaler device; and (3) administering the dosing amount to the patient;

wherein the vapour impermeable sachet is adapted to exclude or minimise excess air to sealingly store the dosing amount within the inhaler device as it forms a (partial) vapour upon storage such that when the vapour impermeable sachet is opened, the dosing amount is available for administration to the patient as a vapour from the inhaler device.

In accordance with the first, second and third aspects, “excess air” is considered to be an unwanted or undesirable volume of air that is (or may be) present intermediate the external housing of the inhaler device and internal surface of the vapour impermeable sachet (for example any air pockets that are external to the inhaler device but captured within the sachet) into which any (partial) vapour that may form as a result of the vapour (or gas) liquid equilibrium that may occur upon storage of the product, may escape, thereby resulting in an unwanted or undesirable loss or reduction in the dosing amount from the inhaler device and hence available for administration to the patient when the sachet is opened to access the inhaler device for use.

Accordingly, in one embodiment the vapour impermeable sachet is adapted to exclude or minimise excess air to prevent a loss or reduction of the dosing amount from within the inhaler device into the excess air volume as a vapour during storage.

In one embodiment according to the first, second and third aspects, the vapour impermeable material is capable of being shrink-wrapped to sealingly store the dosing amount as a (partial) vapour within the inhaler device. In another embodiment according to the first, second and third aspects, the vapour impermeable material is capable of being heat-sealed to sealingly store the dosing amount as a (partial) vapour within the inhaler device. In yet another embodiment according to the first, second and third aspects, the vapour impermeable material is capable of being ultrasonically welded to sealingly store the dosing amount as a (partial) vapour within the inhaler device.

In one embodiment according to the first, second and third aspects the vapour impermeable material is a vapour impermeable film or foil.

In one embodiment according to the first, second and third aspects, the inhalable liquid is a halogenated volatile liquid. In a further embodiment the halogenated volatile liquid is selected from the group consisting of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane),

WO 2018/132867

PCT/AU2018/050025 sevoflurane (fluoromethyl-2,2,2-trifluoro-1-(trifluroromethyl)ethyl ether), desflurane (2difluoromethyl-1,2,2,2-tetrafluoroethrylether), isoflurane (1-chloro-2,2,2trifluoroethyldifluoromethyl ether), enflurane (2-chloro-1,1,2-trifluoroethyldifluoromethyl ether) and methoxyflurane (2,2-dichloro-1,1-difluoroethylmethyl ether). In a preferred embodiment, the inhalable liquid is methoxyflurane for use as an analgesic.

BRIEF DESCRIPTION OF THE FIGURES

FIGURE 1 shows a prior art inhaler device, referred to as the Green Whistle™ inhaler device (Medical Developments International Limited) that is currently used to administer methoxyflurane.

FIGURE 2 shows a product according to an embodiment of the invention comprising an inhaler device sealingly stored within a vapour impermeable sachet for storage (Figure 2A); opening the vapour impermeable sachet by tearing (Figure 2B); and access to the inhaler device from the opened vapour impermeable sachet for use (Figure 2C).

FIGURE 3 shows a top view of a product according to an embodiment of the invention comprising an inhaler device sealingly stored within a vapour impermeable sachet (Figure 3A); a rear- (or front-) perspective view along cross-sectional line A-A (Figure 3B); and a side profile view (Figure 3C).

FIGURE 4 shows a cross-sectional view of an inhaler device (along its length) for use in a product or a method according to an embodiment of the invention to illustrate use of the product by the patient in administration mode, i.e., inhalation of the inhalable liquid as a vapour from within the inhaler device by the patient in the direction of the arrows shown following opening of and removal of the inhaler device from the vapour impermeable sachet.

FIGURE 5 presents the stability (storage) performance results under accelerated conditions of a product according to an embodiment of the invention.

FIGURE 6 presents the comparative drug delivery (administration) performance results of a product according to an embodiment of the invention and the current Green Whistle™ inhaler device of Figure 1 (without the ‘AC’ chamber).

DETAILED DESCRIPTION

Inhaler devices that are useful for administering inhalable liquids may be generally considered to operate by either passive or active means in order to deliver the active agent(s) to a patient. Inhaler devices with active means may include pressurized, moving, mechanical, heating and/or electrical means to, for example, nebulise, vaporize and/or generally deliver the active agent(s). In contrast, inhaler devices with passive means rely

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PCT/AU2018/050025 solely on the vaporisation or evaporation of the active agent(s) at ambient conditions and respiration of the patient to deliver the active agent(s).

The Analgizer™ inhaler device (Abbott Laboratories Corporation) is an example of a device that operates by passive means to deliver an inhalable liquid. According to the USPTO TESS database, the Analgizer™ was a registered, now lapsed, trademark in respect of an inhaler for the supervised self-administration of inhalation anaesthesia and was first used in 1968. The Analgizer™ was a very simple device that consisted of a white cylindrical polyethylene open-ended tube having a mouthpiece and an absorbent wick of polypropylene which was tightly rolled into a ‘Swiss-roll’ shape, i.e. cross-sectional view. The inhalation anaesthetic, methoxyflurane (15mL), was poured into the open ended base of the inhaler and onto the tightly wound wick, just prior to use. A patient was then able to self-administer the liquid anaesthetic by inhaling through the mouthpiece.

The Green Whistle™ inhaler device (Medical Developments International Limited) was subsequently developed during the 1990s and has since been used in Australia for the delivery of Penthrox®/™ (methoxyflurane) as an analgesic (1.5mL or 3mL, storage brown glass vial container with screw cap). Although similar in its simplicity of design to the Analgizer™, the Green Whistle™ device includes certain functional improvements such as the inclusion of a one-way valve at the base end to prevent drug vapour loss from the device upon patient exhalation and an activated carbon (‘AC’) chamber designed to be externally fit into a dilution hole in the mouth piece to filter exhaled drug vapours. Additional design modifications to the base end included the introduction of cap lugs to assist removal of the cap from the glass vial used to store the drug dose to be delivered, a dome to facilitate the spread of the poured liquid onto the ‘S-shaped’ wick circumference (i.e. cross-sectional view) or, in the alternative to a dome, an inlet nipple to allow for the attachment of a breathable gas line to direct the gas through the device. The Green Whistle™ device is designed for single patient use.

Methoxyflurane (Penthrox®/™, Medical Developments International Limited) offers a non-narcotic, i.e. non-opioid analgesic alternative to common analgesics such as morphine and fentanyl. Methoxyflurane also presents an alternative to analgesics which are administered in oral tablet form or intravenously to a patient and may therefore be particularly useful when rapid pain relief is required in clinical, surgical (e.g. pre- and postoperative) and/or emergency settings (e.g. emergency department and triage management as well as by first-responders such as paramedics and search and rescue teams).

The Green Whistle™ device is shown in Figure 1 and is currently the only device that is commercially available to administer methoxyflurane. According to the device’s instructions

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PCT/AU2018/050025 for use, the administrator is required to hold the methoxyflurane bottle upright to use the base of the inhaler to loosen the bottle cap and then to remove the cap by hand before tilting the inhaler to a 45° angle and pouring the contents of the bottle into the base while rotating the device. An AC-chamber may be optionally fitted externally to the device either beforehand or afterwards. While the device is effective, the number of steps and separate components may present handling difficulties for the administrator or self-administrator including the potential for a reduction in the dosing amount caused by spillage or incorrect loading, for example, in high-stress and/or emergency settings.

The present invention provides a new product for the storage and administration of inhalable liquids as a vapour to a patient offering one or more advantages or improvements over known inhalers, in particular known inhalers for the delivery of halogenated volatile liquids such as methoxyflurane for use as an analgesic.

The product is capable of both storing and administering an inhalable liquid, such as a halogenated volatile liquid, as a vapour by providing an inhaler device comprising a passive evaporation support material located within the inhaler device and pre-loaded with the required dosing amount of the liquid wherein the inhaler device is stored within a vapour impermeable sachet to sealingly store the dosing amount as it forms a (partial) vapour upon storage within the inhaler device.

In storage mode, the product comprising the inhaler device sealingly stored within a vapour impermeable sachet, functions as a sealed storage container for the dosing amount of inhalable liquid (and its vapour) so that the device is primed and ready for immediate delivery of the dosing amount of drug in (partial) vapour form to the patient upon opening the sachet.

In administration mode, the vapour impermeable sachet is opened to access the inhaler device sealingly stored therein and remove therefrom for administration of the dosing amount of drug in (partial) vapour form to the patient, that is to allow air to be drawn into the device (for example as illustrated in Figure 4) upon inhalation by the patient through the device when required for use.

The vapour impermeable sachet is adapted to exclude or minimise any excess air (that is, excess air intermediate the external housing of the inhaler device and internal surface of the vapour impermeable sachet, for example, any air pockets that may form within the vapour impermeable sachet that are external to the inhaler device) during the process of sealingly storing the device within the vapour impermeable sachet.

The exclusion or minimisation of the presence of excess air is considered to offer the advantage of preventing any loss or reduction in the stored vapour from within the inhaler

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PCT/AU2018/050025 device during storage and hence dosing amount available for delivery to the patient when the sachet is opened to access the inhaler and allow for administration of the inhalable liquid as a vapour from the inhaler to the patient.

The product is therefore adapted for storing the inhalable liquid as a (partial) vapour within the device and administering the dosing amount in the form of the stored (partial) vapour upon opening the vapour impermeable sachet to access the device and subsequently as a vapour from passive release of the liquid from the passive evaporation support material during use of the device i.e. upon inhalation by a patient.

Without wishing to be bound by theory, as a result of the vapour (or gas) - liquid equilibrium that occurs upon storage, the inhalable liquid forms a (partial) vapour within the inhaler device such that the stored partial vapour is available (primed for use) for direct (immediate) administration to a patient upon opening the vapour impermeable sachet. It will be understood that the relative amount of stored liquid to vapour in the inhaler device during storage will depend on the storage conditions (i.e. temperature and/or pressure dependent).

When the inhaler device is required for use, the vapour impermeable sachet is opened and the device removed therefrom to allow for an air/vapour flow pathway through the device and an initial delivery of the stored partial vapour to the patient when the patient first inhales through a mouthpiece end of the device. Subsequent delivery of the dosing amount that is in liquid form may then occur as the liquid is released as a vapour from the passive evaporation support material during use of the device (i.e. inhalation of the released vapour by the patient).

The product is therefore considered to offer one or more advantages, for example, an easy to use, pre-loaded (i.e. primed for use) for rapid administration, readily portable inhaler which may also provide further reductions in manufacturing costs, shipping, packaging, storage and disposal costs as well as material wastage, by avoiding the need to store the liquid in a separately manufactured container.

Definitions

Unless otherwise herein defined, the following terms will be understood to have the general meanings which follow.

Active agent’ refers to therapeutic agents and non-therapeutic agents and compounds, formulations and compositions comprising them.

Alleviate’, Alleviation’ and variations thereof refers to relieving, lessening, reducing, ameliorating or an improvement in the symptom(s) and/or underlying cause(s) of a condition and/or disease in a patient.

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PCT/AU2018/050025 ‘Delivery dose’ refers to the dose of inhalable liquid or active agent for administration to a patient.

‘Filter’, ‘Filtering’ and variations thereof refers to the ability of a substance to absorb, adsorb, capture, trap, scavenge, scrub or partially or entirely remove the inhalable volatile liquid vapour from the exhaled breath of a patient upon exhalation.

‘Halogenated volatile liquids’ refers to volatile liquids which (i) comprise at least one halogen atom selected from the group consisting of a chlorine (Cl), bromine (Br), fluorine (F) and iodine (I) atoms, or (ii) comprise an active agent which comprises at least one halogen atom selected from the group consisting of a chlorine (Cl), bromine (Br), fluorine (F) and iodine (I) atoms. In some embodiments, halogenated, particularly fluorinated, hydrocarbons and halogenated, particularly fluorinated, ethers may be preferred. In some embodiments, halogenated ethers may be particularly preferred and include but are not limited to, halothane (2-bromo-2-chloro-1,1,1-trifluoroethane), sevoflurane (fluoromethyl-2,2,2-trifluoro1-(trifluroromethyl)ethyl ether), desflurane (2-difluoromethyl-1,2,2,2-tetrafluoroethrylether), isoflurane (1-chloro-2,2,2-trifluoroethyldifluoromethyl ether), enflurane (2-chloro-1,1,2trifluoroethyldifluoromethyl ether) and methoxyflurane (2,2-dichloro-1,1-difluoroethylmethyl ether).

‘Inhalable liquid’ refers to liquids that comprise active agents or that are themselves the active agent and that are readily inhalable or capable of being or adapted to be inhaled by a patient. In some embodiments, inhalable volatile liquids, particularly halogenated volatile liquids are preferred.

‘Inhalation’, ‘Inhalable’ and variations thereof refers to the intake of, for example but not limited to air, breathable gases, inhalable liquids, by a patient and includes both oral and nasal inhalation. In some embodiments, oral inhalation is particularly preferred.

‘Patient’ refers to both human and veterinary patients. In some embodiments, human patients may be particularly preferred. Reference to a patient will therefore be understood to mean the person or animal to whom the inhalable liquid is administered to and in the case of human patients, will be understood to include administration by self-administration.

‘Pharmaceutical agent’ refers to a drug, or a compound, formulation or composition that comprises a drug, for the treatment of symptom(s) and/or underlying cause(s) of a condition and/or disease in a patient. The term pharmaceutical agent may be used interchangeably with therapeutic agent or active agent.

WO 2018/132867

PCT/AU2018/050025 ‘Respiratory’, ‘Respirational’ and variations thereof refers to the act of respiring, breathing, inhaling and exhaling, such as for example but not limited to air, breathable gases, inhalable liquids and active ingredients, by a patient.

‘Room temperature’ refers to ambient temperatures which may be, for example, between 10°C to 40°C but more typically between 15°C to 30°C.

‘Therapeutic agent’ refers to an active agent, or a compound, formulation or composition (including biological compounds, formulations and compositions) that comprises an active agent, that is capable of treating a patient or offers a therapeutic or medical benefit to a patient or that has or that requires regulatory and/or marketing approval for therapeutic use in a patient. Therapeutic agents include pharmaceutical agents. In contrast, a ‘Nontherapeutic agent’ will be understood to mean an active agent which may not have or require regulatory and/or marketing approval for a therapeutic use such as, for example, smokeless tobacco products and electronic cigarettes, or does not have a recognised or identified therapeutic use but may be used by a patient for a non-therapeutic reason such as general health, wellbeing or physiological benefit such as, for example, nutraceutical products.

‘Treat’, ‘Treatment’ and variations thereof refers to the alleviation, modulation, regulation or halting of the symptom(s) and/or underlying cause(s) of a condition and/or disease in a patient. In some embodiments treatment may include preventative or prophylactic treatment.

‘Volatile liquids’ refers to substances that predominantly exist in a liquid form but readily form vapours, evaporate or vaporize such that they partially exist in a vapour form under ambient conditions for example, at room temperature and at normal atmospheric pressures.

Embodiments

Embodiments will now be described with reference to the following non-limiting examples.

The present product comprises a passive evaporation support material pre-loaded with the inhalable liquid to provide a portable, ready-to-use, all-in-one, drug storage and delivery device. In comparison to the prior inhaler devices for methoxyflurane, the present product provides easy and rapid administration, in particular self-administration when rapid pain relief is required, for example, in emergency, non-hospital, isolated, outdoor environment, sporting, humanitarian aid and/or field operation environments.

In one embodiment the vapour impermeable sachet comprises a vapour impermeable material. In one embodiment the vapour impermeable material is a vapour impermeable film. Vapour impermeable films may be a single layer or a laminate film comprising at least

WO 2018/132867

PCT/AU2018/050025 one vapour impermeable layer. In another embodiment the vapour impermeable material is a foil.

In one embodiment the vapour impermeable material is in the form of a sachet with an opening to allow for insertion of the inhaler device comprising the inhalable liquid thereinto prior to sealing the opening to enclose the device within the vapour impermeable sachet for storage.

In another embodiment the vapour impermeable material is in the form of a single sheet to surround the inhaler device comprising the inhalable liquid therein prior to sealing the sheet to enclose the device within the vapour impermeable sachet for storage.

In another embodiment the vapour impermeable material is in the form of two sheets to allow for placement of the inhaler device comprising the inhalable liquid there-between prior to sealing the sheets to enclose the device within the vapour impermeable sachet for storage.

The vapour impermeable sachet may be formed (or sealed) from the vapour impermeable material by suitable sealing processes available to seal vapour impermeable materials (such as films or foils) and to further exclude or minimise excess air for the purpose(s) as described herein. In one embodiment the vapour impermeable material is adapted to form the vapour impermeable sachet upon sealing by a suitable sealing process, such as is described herein.

In one embodiment the vapour impermeable sachet is formed (or sealed) such that a ‘closefit’ around the external housing of the inhaler device is achieved to exclude or minimise excess air. In one embodiment the inhaler device is sealed within the vapour impermeable sachet such that a ‘close-fit’ between an external housing of the inhaler device and an internal surface of the vapour impermeable sachet is achieved to exclude or minimise the excess air.

Suitable sealing processes may include, for example, by a physical process (such as, for example, by shrink-wrapping or by welding, for example, thermal welding, ultrasonic welding) or by a chemical process (such as, for example, by adhesives).

In one embodiment the vapour impermeable material is adapted to form the vapour impermeable sachet upon sealing by a process selected from the group consisting of thermal welding, ultrasonic welding and shrink-wrapping wherein the process is adapted to exclude excess air.

In one embodiment the inhaler device is sealingly stored within the vapour impermeable sachet by a process selected from the group consisting of thermal welding, ultrasonic welding and shrink-wrapping wherein the process is adapted to exclude excess air.

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In one embodiment the vapour impermeable sachet comprises a vapour impermeable material (such as a polymeric film or foil) that is suitable for shrink-wrapping. In another embodiment the vapour impermeable sachet comprises a vapour impermeable material (such as a polymeric film or foil) that is suitable for thermal-weld sealing. In yet another embodiment vapour impermeable sachet comprises a vapour impermeable material (such as a polymeric film or foil) that is suitable for ultrasonic-weld sealing.

In one embodiment the vapour impermeable sachet comprises a therompolymer.

In one embodiment, the vapour impermeable sachet comprises a polymer selected from the group consisting of polyethylene terephthalate (‘PET’), polypropylene (‘PP’) and polyethylene (‘PE’). In one embodiment the vapour impermeable sachet comprises polyethylene terephthalate (‘PET’). In other embodiment the vapour impermeable sachet comprises polypropylene (‘PP’). In yet another embodiment the vapour impermeable sachet comprises polyethylene (‘PE’).

Examples of vapour impermeable films include but are not limited to polymeric films, metal foils (such as, for example, aluminium, nickel and alloys thereof) and combinations, including co-extruded polymeric films and/or foils such as laminate films, thereof. In one embodiment the vapour impermeable film is a single layer selected from a polymeric film or a metal foil. In another embodiment the vapour impermeable film is a laminate film comprising two or more layers selected from a polymeric film, a metal foil and combinations, including coextruded polymeric films and/or foils, thereof. The laminate film may comprise a weldable layer made from a suitable weldable foil or polymeric film such as, for example, LLDPE. A weldable layer may assist with sealing the layers of a laminate together and/or sealing a vapour impermeable film comprising a weldable layer to the device. Processes suitable for welding include thermal and ultrasonic welding. The laminate film may comprise an adhesive layer including a peelable adhesive layer.

In one embodiment the polymeric film has a MVTR of less than 100 g/m²/24h, preferably less than 50 g/m²/24h. In one embodiment the polymeric film comprises a polymer selected from the group consisting of a polyolefin, a polymeric phthalate, a fluorinated polymer, a polyester, a nylon, a polyvinyl, a polysulfone, a natural polymer and combinations, including co-extruded polymers thereof including biaxially orientated polymers such as, for example, biaxially orientated polypropylene (BOPP). In one embodiment the polymeric film comprises a polymer selected from the group consisting of PP, PE, LDPE, LLDPE, HDPE, BOPP, 4-methylpentene, polymethylpentene polycyclomethylpentene, PEN, PET, PETP, PEI, PBT, PTT, PCT, Kel-F, PTFE, cellulose acetate, POM, PETG, PCTG, PCTA, nylon, PVA, EVOH, starch, cellulose, proteins and combinations, including co-extruded polymers, thereof.

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In one embodiment the vapour impermeable film comprises PET. In another embodiment the vapour impermeable film comprises PET and a metal foil layer, preferably an aluminium foil layer. In one embodiment the vapour impermeable film comprises metalised PET (Met

PET).

In one embodiment the vapour impermeable film comprises a co-extruded polymer layer adhered to a metalised PET layer adhered to an externally peelable LLDPE layer. In a further embodiment the co-extruded polymer layer is a biaxially orientated polymer, preferably BOPP. In another embodiment the vapour impermeable film comprises a layer of BOPP adhered to a metalised PET layer adhered to an externally peelable LLDPE layer.

In one embodiment the vapour impermeable sachet optionally comprises an introduced point of weakness to aid with opening the sachet (for example by tearing, perforating or ripping) to access the device when the device is required for use. Suitable means to introduce a point of weakness into the vapour impermeable sachet will be familiar to those in the art and may include, for example, a thin-ness (i.e. thinner section of material), perforations or a cut-out section.

In one embodiment, as illustrated in Figure 2 the vapour impermeable sachet comprising the inhaler device (Figure 2A) is opened by tearing (Figure 2B) to access the inhaler device for use (Figure 2C).

In one embodiment, as illustrated in Figure 3A, the vapour impermeable sachet (5) comprises a point of weakness (6) to assist opening and is formed (or sealed) such that a ‘close-fit’ around the external housing (7) of the inhaler device (8) is achieved to exclude or minimise excess air. A cross-sectional rear-(or front-) perspective view of the product of Figure 3A along A-A is shown in Figure 3B and a side profile view of the product is further provided in Figure 3C.

In one embodiment the passive evaporation support material stored within the inhaler device is adapted to form a single longitudinal airflow/vapour pathway though the device when the vapour impermeable sachet is opened. In another embodiment, the passive evaporation support material is adapted to form at least two independent longitudinal airflow/vapour pathways though the inhaler device when the vapour impermeable sachet is opened. In yet another embodiment, the passive evaporation support material is adapted to form three or more independent longitudinal airflow/vapour pathways though the inhaler device when the vapour impermeable sachet is opened.

In one embodiment the passive evaporation support material stored within the inhaler device is adapted to provide a single longitudinal airflow/vapour pathway though the inhaler device when the vapour impermeable sachet is opened and in one embodiment is planar.

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In another embodiment the passive evaporation support material is adapted to form at least two independent longitudinal airflow/vapour pathways, three or more independent longitudinal airflow/vapour pathways, through the inhaler device when the vapour impermeable sachet is opened. Numerous examples of cross-sectional shapes which are capable of forming at least two, three or more independent longitudinal airflow/vapour pathways may be envisaged, some of which follow. The two, three or more independent longitudinal airflow/vapour pathways may be formed by the passive evaporation support material adopting a cross-sectional shape selected from a letter of the alphabet or a single digit number such as, for example although not limited to, an A-shape, B-shape, S-shape, Z-shape, figure-2 , figure-5 and figure-8 which are capable of forming at least two independent airflow/vapour pathways, and a K-shape, M-shape, V-shape, W-shape, Xshape, Y-shape and figure-3 which are capable of forming three or more independent longitudinal airflow/vapour pathways through the inhaler device when the vapour impermeable sachet is opened.

In one embodiment the passive evaporation support material is adapted to provide three or more independent longitudinal airflow/vapour pathways. The pathways may be formed as independent conduits through the passive evaporation support material itself or the pathways may be formed by the evaporative means making contact with an internal surface of the vapour chamber. Accordingly, in one embodiment, the passive evaporation support material comprises three or more longitudinal conduits wherein the conduits are formed within the passive evaporation support material or are formed by the passive evaporation support material together with an internal surface of the inhaler device or a combination thereof when the vapour impermeable sachet is opened.

The passive evaporation support material may be made from any material that is suitable for absorbing the inhalable liquid and passively releasing it as a vapour. Materials which have wicking properties may be suitable passive evaporation support material for use in the present product. Wicking properties will generally be understood to include the ability of a material to facilitate or enhance the rate of evaporation or vaporisation of a liquid from its surface by distributing the liquid, whether by drawing, spreading, pulling or otherwise, throughout the material from its initial point of contact and/or as it evaporates from an exposed surface area of the material. Accordingly, in one embodiment the passive evaporation support material is a wicking material. In one embodiment the wicking material is a wicking felt or a porous polymeric material. In a preferred embodiment the wicking material is a polypropylene wicking felt.

It will be understood that numerous design variations and modifications of inhaler devices may be suitable for use in the present product, process and/or method of the invention.

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In one embodiment the inhaler device is the Green Whistle™ inhaler device (without the externally fitted ‘AC’-chamber). The ‘AC’-chamber may optionally be fitted for administration of the inhalable liquid (methoxyflurane) to the patient in the usual manner following opening of and removal of the device from the vapour impermeable sachet.

Other inhaler devices that may be suitable for use in the present product, process and/or method of the invention may include, for example, a device described in international application numbers, PCT/AU2016/050636, PCT/AU2016/050637, PCT/AU2016/050638 or PCT/AU2016/050639.

In general, the inhaler device will typically comprise an external housing and an internal air chamber within which the passive evaporation support material pre-loaded with inhalable liquid is located and into which the (partial) vapour forms upon storage of the product. The external housing will typically comprise a mouthpiece end with a mouthpiece (or vapour inhalation) opening which is adapted to allow the patient to inhale the vapour from the internal air chamber. The external housing will also typically comprise an air inlet to allow for the intake of air into the internal air chamber and formation of an air/vapour pathway through the inhaler device, more particularly through the internal air chamber comprising the vapour, to allow for the delivery of the vapour to the patient upon inhalation when the inhaler is in use (i.e. following opening of and removal of the device from the vapour impermeable sachet).

In one embodiment the inhaler device comprises:

(a) an external housing; and (b) an internal air chamber within which the passive evaporation support material pre-loaded with the dosing amount of inhalable liquid is located and into which the (partial) vapour forms upon storage of the product;

wherein the external housing further comprises:

(i) a mouthpiece end with a mouthpiece (or vapour inhalation) opening adapted to allow the patient to inhale the dosing amount as a vapour from the internal air chamber; and (ii) an air inlet to allow for the intake of air into the internal air chamber and formation of an air/vapour pathway through the inhaler device to allow for the delivery of the vapour to the patient upon inhalation when the inhaler is in use.

In one embodiment the external housing generally adopts substantially the same crosssectional shape along its length. In one embodiment the cross-sectional shape of the external housing is selected from circular, semi-circular, elliptical, semi-elliptical, oval, ovoidal, square, rectangular, trapezoidal, triangular and combinations thereof. Shapes having square corners may also be replaced with rounded corners, for example, a rectangle

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PCT/AU2018/050025 having a square corner replaced by a rounded one may be referred to as a rounded rectangular shape. In one embodiment the cross-sectional shape of the elongated housing is selected from cylindrical, rectangular, rounded rectangular, trapezoidal and rounded trapezoidal. The cross-sectional shape of the mouthpiece end may be the same or different to the rest of the elongated housing. In one embodiment, the mouthpiece end is tapered towards the vapour inhalation opening. In a preferred embodiment the cross-sectional shape of the vapour inhalation opening is adapted to fit a conventional aerosol or nebuliser face mask.

In one embodiment the inhaler device is as illustrated in Figure 4. The cross-sectional view presented in Figure 4 shows the inhaler device (9) in use by a patient. The passive evaporation support material pre-loaded with the inhalable liquid (10) is positioned within an air intake chamber (11) of the device. The air intake chamber comprises an air inlet opening (12) which enables air/vapour to flow through the air intake chamber (external air flows into the device via the air inlet opening and across the exposed surface(s) of the passive evaporation support material) and into the mouthpiece chamber (13) once the vapour impermeable sachet is opened to enable delivery of the vapour that is released from the passive evaporation support material to the patient when the patient inhales through mouthpiece opening (14). The direction of the air/vapour pathway upon inhalation by the patient is illustrated by the arrow (15).

The inhaler devices for use in the product or method may be made from various materials. However, suitable material(s) may be selected by considering whether they are chemically inert, stable and impervious with reference to the inhalable liquid to be stored and/or delivered. M ate ria I (s) may also be selected based on their suitability for medical device applications such as by reference to whether they meet approved standards for medicalgrade human use by a regulatory authority like the FDA.

Examples of materials which may be suitable for making the inhaler device include but are not limited to polymers (including homopolymers and heteropolymers i.e. co-polymers), composites (including nanocomposites), metals (including alloys thereof) and combinations thereof. In one embodiment, the device is made from polymers (including homopolymers and heteropolymers i.e. co-polymers), composites (including nanocomposites such as polymers in combination with clay), metals (including aluminium and alloys thereof) and combinations thereof. In a further embodiment, the device is optionally internally lined or coated with one or more material(s) selected from the group consisting polymers (including homopolymers and heteropolymers i.e. co-polymers), composites (including nanocomposites such as polymers in combination with clay), metals (including aluminium, nickel and alloys thereof for example, stainless steel), oxides (including aluminium oxides,

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PCT/AU2018/050025 silicon oxides), resins (including epoxyphenolic resins and ionomeric resins such as Surlyn®, trademark of DuPont), lacquers and enamels.

Polymers are particularly suited to large scale manufacturing of inhaler devices and the polymeric films described herein, in particular the inhaler device and the vapour impermeable film, by injection moulding, blow moulding and extrusion processes. They may also be suitable for manufacturing the inhaler device on a smaller scale by 3D printing techniques. Further, polymers may be recycled following disposal of the product.

Examples of polymers for use in making the inhaler device and polymeric films described herein may include but are not limited to the following polymers and combinations (including co-extruded polymers) thereof: polyolefins such as polypropylene (‘PP’), polyethylene (‘PE’) including low density (‘LDPE’), linear low density (‘LLDPE’) and high density polyethylene (‘HDPE’), biaxially orientated polypropylene (‘BOPP’), 4-methylpentene, polymethylpentene, polycyclomethylpentene; polymeric phthalates such as polyethylene naphthalates (‘PEN’), polyethylene terephthalate (‘PET’) (also known as (‘PETE’)), polyethylene terephthalate polyester (‘PETP’), polyethylene isophthalate (‘PEI’), polybutylene terephthalate (‘PBT’), polytrimethylene terephthalate (‘PTT’), polycyclohexylenedimethylene terephthalate (‘PCT’); fluorinated polymers including polymers fluorinated after manufacture (e.g. fluorination postmoulding), fluorinated ethylene-propylene, chlorotrifluoroethylene (‘Kel-F’), polytetrafluoroethylene (‘PTFE’); polyesters including cellulose acetate, polyoxymethylene (‘POM’) and polyesters containing a terephthalate ester group including co-polymers such polyethylene terephthalate glycol co-polyester (‘PETG’), polycyclohexylenedimethylene terephthalate glycol modified (‘PCTG’) and polycyclohexylenedimethylene terephthalate/isophthalic acid (‘PCTA’); nylons including amorphous nylon; polyvinyls including polyvinyl alcohol (‘PVA’) and ethylene vinyl alcohol (‘EVOH’); polysulfones including polyethersulfone (‘PES’); and natural polymers including starch, cellulose and proteins. Suitable polymers may also include polymers with a moisture vapour transmission rate (‘MVTR’, also known as water vapour transmission rate ‘WVTR’) of less than 100 g/m²/24h, preferably less than 50 g/m²/24h.

Accordingly, in one embodiment the device is made from one or more polymers wherein the device further comprises an optional internal lining or coating with one or more material(s) selected from the group consisting polymers (including homopolymers and heteropolymers (also known as co-polymers) and combinations thereof including co-extruded polymers), composites (including nanocomposites such as polymers in combination with clay), metals (including aluminium, nickel and alloys thereof), oxides (including aluminium oxides, silicon oxides), spray coatings, resins (including epoxyphenolic resins and ionomeric resins such as Surlyn®, trademark of DuPont), lacquers and enamels.

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In one embodiment the polymer is selected from a polyolefin, a polymeric phthalate, a fluorinated polymer, a polyester, a nylon, a polyvinyl, a polysulfone, a natural polymer and combinations, including co-extruded polymers thereof. In one embodiment the polymer has a MVTR of less than 100 g/m²/24h, preferably less than 50 g/m²/24h. In one embodiment the polyolefin is selected from the group consisting of PP, PE, LDPE, LLDPE, HDPE, 4methylpentene, polymethylpentene, polycyclomethylpentene and combinations, including coextruded polymers thereof such as BOPP. In one embodiment the polymeric phthalate is selected from the group consisting of PEN, PET, PETP, PEI, PBT, PTT, PCT and combinations, including co-extruded polymers, thereof. In one embodiment the fluorinated polymer is selected from Kel-F, PTFE and combinations, including co-extruded polymers thereof. In one embodiment the polyester is selected from the group consisting of cellulose acetate, POM and polyesters containing a terephthalate ester group including PETG, PCTG, PCTA and combinations , including co-extruded polymers, thereof. In one embodiment the nylon is an amorphous nylon. In one embodiment the polyvinyl is selected from PVA, EVOH and combinations, including co-extruded polymers, thereof. In one embodiment the polysulfone is PES. In one embodiment the natural polymer is selected from the group consisting of starch, cellulose, proteins and combinations, including co-extruded polymers, thereof.

In one embodiment the device is made from a single polymer selected from the group consisting of PP, PE, LDPE, LLDPE, HDPE, BOPP, 4-methylpentene, polymethylpentene polycyclomethylpentene, PEN, PET, PETP, PEI, PBT, PTT, PCT, Kel-F, PTFE, cellulose acetate, POM, PETG, PCTG, PCTA, nylon, PVA, EVOH, starch, cellulose, proteins and combinations, including co-extruded polymers, thereof. In another embodiment the device is made from two or more polymers selected from the group consisting of PP, PE, LDPE, LLDPE, HDPE, 4-methylpentene, polymethylpentene polycyclomethylpentene, PEN, PET, PETP, PEI, PBT, PTT, PCT, Kel-F, PTFE, cellulose acetate, POM, PETG, PCTG, PCTA, nylon, PVA, EVOH, starch, cellulose, proteins and combinations, including co-extruded polymers, thereof. In one embodiment, the device is made from a polymer selected from the group consisting of HDPE, PET and combinations thereof. In one embodiment the device comprises PET.

It is envisaged that the present product will be particularly useful for storing and/or administering halogenated volatile liquids. Accordingly, in one embodiment, the product, more particularly the inhaler device and/or the vapour impermeable sachet is made from one or more materials that are compatible with the storage and/or delivery of halogenated volatile liquids to a patient, in particular methoxyflurane for use as an analgesic.

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The present product is considered to be particularly useful for storing and administering a halogenated volatile liquid, particularly methoxyflurane for use as an analgesic. Accordingly, in one embodiment the product comprises a passive evaporation support material preloaded with a halogenated volatile liquid. In a further embodiment the halogenated volatile liquid is selected from the group consisting of halothane (2-bromo-2-chloro-1,1,1trifluoroethane), sevoflurane (fluoromethyl-2,2,2-trifluoro-1-(trifluroromethyl)ethyl ether), desflurane (2-difluoromethyl-1,2,2,2-tetrafluoroethrylether), isoflurane (1-chloro-2,2,2trifluoroethyldifluoromethyl ether), enflurane (2-chloro-1,1,2-trifluoroethyldifluoromethyl ether) and methoxyflurane (2,2-dichloro-1,1-difluoroethylmethyl ether). In a preferred embodiment, the inhalable liquid is methoxyflurane for use as an analgesic.

Suitable dosing amounts of inhalable liquid for administration to a patient by the present product may be determined by reference to, for example, regulatory approved dosage amounts. Suitable dosing amounts of methoxyflurane for use as an analgesic will typically be less than 15ml_ and preferably less than 12ml_ and selected from the group consisting of 0.5ml_, 1ml_, 1.5ml_, 2ml_, 2.5ml_, 3ml_, 3.5ml_, 4ml_, 4.5ml_, 5ml_, 5.5ml_, 6ml_, 6.5ml_, 7ml_, 7.5ml_, 8ml_, 8.5ml_, 9ml_, 9.5ml_, 10ml_, 10.5ml_, 11ml_, 11.5ml_and 12ml_. In one embodiment the dosing amount of methoxyflurane for administration by the present product is selected from the group consisting of 1.5ml_, 3ml_ and 6ml_. In one embodiment, the dosing amount is 3ml_.

Example 1

Figure 1 shows the prior art Green Whistle™ inhaler device (1) (Medical Developments International Limited) which is currently used in Australia for the delivery of Penthrox®/™ (methoxyflurane) as an analgesic (1,5mL or 3mL, storage brown glass vial container with screw cap). When required for use, the delivery dose of methoxyflurane is manually poured into the base end (3) of the device. After the dose is poured into the base end for deposition onto the evaporative means (not shown), the methoxyflurane evaporates so that the patient can self-administer the analgesic by inhaling the air/vapour mix through the mouthpiece (2). Provided that the patient continues to breathe through the mouthpiece, any exhaled air/vapour mix will exit the device via the (optional) externally fitted chamber containing activated carbon ‘AC-chamber’ (4).

Example 2

A prototype product according to an embodiment of the invention was assembled by sealing an inhaler device having an internally located polypropylene wick pre-loaded with a dosing amount of methoxyflurane, within a vapour impermeable sachet as follows:

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Inhaler device·. A standard Green Whistle™ inhaler device (as shown in Figure 1) was preloaded with a dosing amount of methoxyflurane (i.e. by pouring the dosing amount, 3ml_, in the form of a liquid, onto the wick).

Vapour Impermeable Sachet. The pre-loaded inhaler device was placed within a vapour impermeable polymeric film comprising PET and the vapour impermeable sachet was formed by heat-sealing the film around the external housing of the device to exclude or minimise excess air and sealingly store the dosing amount within the inhaler device so that it is primed for delivering the inhalable liquid as a vapour to the patient when the sachet is opened.

Example 3

The stability of the product may be tested using accelerated storage conditions such as for example in an oven set at 60°C and sampled at time periods appropriate for marketing and/or regulatory approval.

The stability of the product of Example 2 was tested using six (6) products and the initial mass of each product measured. The products were then held for twenty (20) days at 60°C being equivalent to twelve (12) months shelf-life. The results are presented in Figure 5 (for each product tested labelled “Product 1”, “Product 2” etc. respectively). Four (4) out of the six (6) prototype products tested maintained their original (initial) mass. The loss in mass that was observed for the two (2) remaining devices was attributed to ineffective/incomplete sealing which resulted in the methoxyflurane escaping as a vapour from the device (and corresponding reduction in dosing amount).

Example 4

The ability of an inhaler device to deliver methoxyflurane may be tested using a breath simulator system such as a pulmonary waveform generator system.

The delivery of methoxyflurane (% concentration) by:

(a) the Green Whistle™ inhaler device of Figure 1 (without the ‘AC’ chamber) following manual loading (by pouring) with methoxyflurane according to its instructions for use; and (b) an inhaler device pre-loaded with methoxyflurane selected from Example 3 (product that had maintained its weight post-stability testing) following opening of the sachet and removal of the device;

was measured respectively using a pulmonary waveform generator system.

The devices were tested as follows. The pulmonary waveform generator was set to “Adult” flow conditions (14 breaths per minute) and the concentration logging software and Datex Sensor commenced. For each test, the polypropylene wick was pre-loaded with

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PCT/AU2018/050025 methoxyflurane (3mL) to be delivered and the mouthpiece end of the device then inserted into the opening of the pulmonary waveform generator. Concentration logging was commenced for the first minute for the first breaths concentration and then for the next 20 minutes for steady state testing.

The results are presented in Figure 6 (Green Whistle™ inhaler device and product from Example 3 labelled “Product”). The results show that the devices delivered methoxyflurane. Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise” and variations thereof such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not to the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication or information derived from it, or to any matter which is known is not and should not be taken as an acknowledgement or admission or any form of suggestion that prior publication, or information derived from it, or known matter, forms part of the common general knowledge in the field of endeavour to 15 which this specification relates.

Claims

(1) sealingly storing an inhaler device within a vapour impermeable sachet wherein the inhaler device comprises a passive evaporation support material that is located internally within an external housing of the device and is pre-loaded with the dosing amount of the liquid;

(1) providing an inhaler device comprising an external housing and an internally located passive evaporation support material;

(1) an inhaler device;

1. A product for the storage and administration of a dosing amount of an inhalable liquid to a patient, said product comprising:
(2) opening the vapour impermeable sachet to access the inhaler device; and (3) administering the dosing amount to the patient;

wherein the vapour impermeable sachet is adapted to exclude or minimise excess air to sealingly store the dosing amount within the inhaler device as it forms a (partial) vapour upon storage such that when the vapour impermeable sachet is opened, the dosing amount is available for administration to the patient as a vapour from the inhaler device.

(2) depositing a dosing amount of an inhalable liquid onto the passive evaporation support material to pre-load the liquid therein to allow for delivery of the inhalable liquid as a vapour to the patient when the inhaler device is in use;

2. The product according to claim 1 wherein the inhaler device is sealed within the vapour impermeable sachet such that a ‘close-fit’ between an external housing of the inhaler device and an internal surface of the vapour impermeable sachet is achieved to exclude or minimise the excess air.

(2) a passive evaporation support material located within the inhaler device and pre-loaded with the dosing amount of the liquid; and (3) a vapour impermeable sachet;

wherein the inhaler device is sealed within the vapour impermeable sachet and further wherein the vapour impermeable sachet is adapted to exclude or minimise excess air to sealingly store the dosing amount within the inhaler device as it forms a (partial) vapour upon storage of the product such that when the vapour impermeable sachet is opened, the dosing amount is available for administration to the patient as a vapour from the inhaler device.
(3) surrounding the inhaler device with a vapour impermeable material;

3. The product according to claim 1 or claim 2 wherein the inhaler device is sealed within the vapour impermeable sachet by a process selected from the group consisting of thermal welding, ultrasonic welding and shrink-wrapping wherein the process is adapted to exclude excess air.
(4) excluding or minimising excess air intermediate the external housing and vapour impermeable material; and (5) sealing the vapour impermeable material to form a vapour impermeable sachet to sealingly store the dosing amount within the inhaler device;

wherein the excess air is excluded or minimised to sealingly store the dosing amount within the inhaler device as it forms a (partial) vapour upon storage of the product such that when the vapour impermeable sachet is opened, the dosing amount is available for administration to the patient as a vapour from the inhaler device.

4. The product according to any one of claims 1 to 3 wherein the vapour impermeable sachet comprises a vapour impermeable material.
5. The product according to claim 4 wherein the vapour impermeable material is suitable for shrink-wrapping.
6. The product according to claim 4 wherein the vapour impermeable material is suitable for thermal-weld sealing.
7. The product according to claim 4 wherein the vapour impermeable material is suitable for ultrasonic-weld sealing.

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8. The product according to any one of claims 4 to 7 wherein the vapour impermeable material is a vapour impermeable film or foil.
9. The product according to any one of claims 1 to 8 wherein the vapour impermeable sachet comprises a thermopolymer.
10. The product according to any one of claims 1 to 8 wherein the vapour impermeable sachet comprises a polymer selected from the group consisting of polyethylene terephthalate (‘PET’), polypropylene (‘PP’) and polyethylene (‘PE’).
11. The product according to any one of claims 1 to 10 wherein the vapour impermeable sachet optionally comprises an introduced point of weakness to aid with opening the sachet.
12. A process for producing the product according to any one of claims 1 to 11 comprising the steps of:
13. The process according to claim 12 wherein the vapour impermeable material is adapted to form the vapour impermeable sachet upon sealing by a process selected from the group consisting of thermal welding, ultrasonic welding and shrink-wrapping wherein the process is adapted to exclude excess air.

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14. The process according to claim 12 or claim 13 wherein the vapour impermeable material is in the form of a sachet with an opening to allow for insertion of the inhaler device comprising the dosing amount prior to sealing the opening to enclose the device within the vapour impermeable sachet for storage.
15. The process according to claim 12 or claim 13 wherein the vapour impermeable material is in the form of a single sheet to surround the inhaler device comprising the dosing amount prior to sealing the sheet to enclose the device within the vapour impermeable sachet for storage.
16. The process according to claim 12 or claim 13 wherein the vapour impermeable material is in the form of two sheets to allow for placement of the inhaler device comprising the inhalable liquid there-between prior to sealing the sheets to enclose the device within the vapour impermeable sachet for storage.
17. A method for the storage and administration of a dosing amount of an inhalable liquid to a patient, said method comprising:
18. The product according to any one of claims 1 to 11, the process according to any one of claims 12 to 16 or the method according claim 17 wherein the inhaler device comprises:

(a) an external housing; and

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PCT/AU2018/050025 (b) an internal air chamber within which the passive evaporation support material pre-loaded with the dosing amount of inhalable liquid is located and into which the (partial) vapour forms upon storage of the product; and wherein the external housing further comprises:

(i) a mouthpiece end with a mouthpiece (or vapour inhalation) opening adapted to allow the patient to inhale the dosing amount as a vapour from the internal air chamber; and (ii) an air inlet to allow for the intake of air into the internal air chamber and formation of an air/vapour pathway through the inhaler device to allow for the delivery of the vapour to the patient upon inhalation when the inhaler is in use.
19. The product, process or method according to claim 18 wherein the inhaler device is the Green Whistle™ inhaler device (without the externally fitted ‘AC’-chamber).
20. The product according to any one of claims 1 to 11, the process according to any one of claims 12 to 16 or the method according claim 17 wherein the wherein the inhalable liquid is a halogenated volatile liquid.
21. The product, process or method according to claim 20 wherein the inhalable liquid is methoxyflurane for use as an analgesic.
22. The product, process or method according to claim 20 wherein the inhalable liquid is methoxyflurane for delivery to a patient in a delivery dose of less than 15ml_.
23. The product according to any one of claims 1 to 11, the process according to any one of claims 12 to 16 or the method according claim 17 wherein the wherein the passive evaporation support material is a polypropylene wicking felt.