WO2020225571A1

WO2020225571A1 - Improvements relating to electronic vapourisers

Info

Publication number: WO2020225571A1
Application number: PCT/GB2020/051130
Authority: WO
Inventors: David Mclaughlin
Original assignee: e-breathe Limited
Priority date: 2019-05-09
Filing date: 2020-05-07
Publication date: 2020-11-12
Also published as: GB201906516D0

Abstract

The present invention discloses a method of determining the amount of Active Pharmaceutical Ingredient (API) in a liquid formulation within a liquid storage reservoir usable with an inhaler with a liquid vapourisation means, and following a plurality of use occasions of the liquid storage reservoir, comprising at least the steps of: (i) determining the theoretical maximum energy (M) required to vapourise all the liquid formulation within a liquid storage reservoir prior to first use; (ii) determining the cumulative actual energy supplied during the use occasions of said liquid storage reservoir (∑E); (iii) determining the difference between M and ∑E; and (iv) determining the amount of API in the liquid storage reservoir using at least: the difference calculated in step (iii), the specific heat of vapourisation of the liquid formulation, and the concentration of API within the liquid formulation.

Description

IMPROVEMENTS RELATING TO ELECTRONIC VAPOURISERS

The present invention pertains to a means for delivering inhaled medicaments to a patient, and, in particular, to an apparatus and method of enhancing electronic vapourisers suitable for use as medical devices.

Background

It is well known that the lungs are an efficient entry point for many active pharmaceutical ingredients (APIs) into the body due to their adaptions for gas exchange including large surface area, moist surface, thin outer tissue layer and close proximity to large blood supply and their place within a double circulatory system which reduces the time taken for a API to be distributed to the body vs e.g. intravenous injection.

There are many available means of delivering APIs to the lungs, the most common being dry powder inhalers (DPI) and metered dose inhalers (MDI). A disadvantage of both DPI and MDI is that they provide a fixed dose of API which cannot be altered. Furthermore, both DPI and MDI require a specific inhalation technique by the user to ensure the API is effectively delivered. Failure to inhale in the prescribed manner often leads to ineffective dosing of API.

Consumer products such as electronic vapourisers, e-cigarettes and e-cigs are an alternative means of delivering APIs to the lungs. Such apparatus have the advantage that the dose of API released during a use occasion can be varied. Furthermore, an electronic vapouriser can provide a dose of API which is effectively delivered at much lower airflows which may be of benefit to respiratory compromised users.

Electronic vapourisers are portable hand-held battery powered devices which heat a liquid formulation, typically nicotine and flavours in an inert base liquid, to form an aerosol which is inhaled by the user. The base liquid can be a mixture of propylene glycol and glycerol. Electronic vapourisers can be activated by either a manual button or an airflow sensor. Upon activation the battery is used to heat a coil of resistive wire to evaporate the liquid formulation.

The amount of API beneficially received by the user is dependent on both the output of the vapouriser and the user inhaling the aerosol in an appropriate manner. Typically, electronic vapourisers do not provide a consistent enough output to meet the demands of a medical device such as those outlined in OECD guidelines. It is desirable to provide a system that can accurately provide a dose of API to a user.

By providing an electronic vapouriser that is sufficiently characterised it is possible to accurately establish the amount of API administered by the apparatus during a use occasion. Of key importance to the accuracy of the estimation of API administration is: i) a known fixed concentration of API within the liquid formulation; ii) a known fixed heat of vapourisation of the liquid formulation; iii) a known thermal mass of the vapourisation means, iv) a known fixed boiling point of liquid formulation, v) a known amount of energy supplied to the vapourisation means; vi) a known resistance of the vapourisation means.

By altering the amount of energy supplied to the vapourisation means during a use occasion it is possible to alter the amount of liquid formulation volatinised and hence the amount of API available for delivery to the user. With sufficient characterisation a relationship can be established that links the input energy to the output API dose.

It is well known that deep lung deposition is best for API delivery as the API is deposited within the alveoli where absorption can readily take place. Alveoli deposition is promoted when the API is inhaled in the mid-part of the inhalation cycle rather than supplying a continuous supply of API throughout the inhalation.

At the beginning of the inhalation cycle the airflow is ramping up and any API supplied during this part may have insufficient airflow to carry it to the alveoli and hence not be available for absorption. At the end of the inhalation cycle, the API supplied may not be followed by sufficient air volume to be swept from the upper respiratory tract and fully deposited within the alveoli; hence some API may be exhaled rather than absorbed by the patient.

To ensure the maximum amount of the administered dose of API is successfully absorbed by the patient it is therefore desirable to only supply the API during the correct portion of the inhalation cycle. The most desirable portion of the inhalation cycle is when the air flow velocity is sufficient to fully entrain the inhalable aerosol and have sufficient air volume following API administration to fully sweep the API into the aveoli.

A user can receive a partial dose when their inhalation falls outside desirable parameters at some point during the release of the API from the inhaler. It would be beneficial to have a means to establish the portion of the dose that is successfully administered as this would give a more accurate reflection of the actual dose received by the user compared to counting the number of use occasions the apparatus was activated.

Successful delivery of API is determined when the user is inhaling in a manner likely to provide deep-lung delivery of the API. The most desirable portion of the inhalation cycle is when the air flow velocity is sufficient to fully entrain the inhalable aerosol and have sufficient air volume following API administration to fully sweep the API into the aveoli. Thus, a successful delivery can be defined as occurring when a) API is administered when the user is inhaling with an airflow greater than or equal to a threshold flow rate (F1) and b) when there is sufficient air volume (V1) inhaled after the API is administered to sweep the upper respiratory tract.

An unsuccessful delivery of API is determined when the user fails to inhale in a manner likely to provide deep-lung delivery of the API. Should the user inhalation airflow rate drop below threshold flow rate F1 the API will not be sufficiently entrained within the airflow to travel to the aveoli. Should the API be administered and the inhalation stop prior to the desired sweep volume V1 the API will be deposited within the upper respiratory tract and not be absorbed fully.

It remains evident that there is an unresolved need for an apparatus and method which can accurately calculate the amount of API successfully delivered to the user of a vapourising device during a use occasion.

According to one aspect of the present invention, there is provided a method of determining the amount of Active Pharmaceutical Ingredient (API) in a liquid formulation within a liquid storage reservoir usable with an inhaler with a liquid vapourisation means, and following a plurality of use occasions of the liquid storage reservoir, comprising at least the steps of:

(i) determining the theoretical maximum energy (M) required to vapourise all the liquid formulation within a liquid storage reservoir prior to first use;

(ii) determining the cumulative actual energy supplied during the use occasions of said liquid storage reservoir (åE);

(iii) determining the difference between M and åE; and

(iv) determining the amount of API in the liquid storage reservoir using at least: the difference calculated in step (iii), the specific heat of vapourisation of the liquid formulation, and the concentration of API within the liquid formulation. Optionally, the method further comprises the step of indicating or communicating the amount API determined in step (iv) either to a user using a feedback means, or to an external system using a communication means, or both.

Optionally, the method further comprises the step of preventing the energisation of the vapourisation means when the difference in energy calculated in step (iii) is less than a pre determined threshold energy value.

Optionally, step (ii) comprises:

(a) determining the total energy (T) supplied to the vapourisation means during a previous use occasion;

(b) determining the initial energy (I) required to raise the temperature of the liquid formulation in the vapourisation means to its boiling point; and

(c) determining the actual energy (E) used during a use occasion from the total energy supplied less the initial energy (E=T-I);

(d) increasing the cumulative value (åE) for the liquid storage reservoir by the actual energy (E) determined in step (c); and

(e) repeating steps (a) to (d) for all previous use occasions of the liquid storage reservoir.

Optionally, the method further comprises the determination of one or more of total energy (T), initial energy (I) and actual energy (E) utilises one or more of the group selected from: the thermal mass of the vaporisation means, the boiling point of the liquid formulation, the specific heat capacity of the liquid formulation, the specific heat of vaporisation of the liquid formulation, and the concentration of API within the liquid formulation.

Optionally, the method further comprises storing in an information storage means within the inhaler or within the liquid formulation reservoir, one or more of the group selected from: the thermal mass of the vapourisation means; the specific heat of vapourisation per unit volume of liquid formulation; the concentration of API within the liquid formulation; the boiling point of the liquid formulation; the total energy required to vapourise fully the liquid formulation contained within the liquid storage reservoir (M); the amount of initial energy for the vapourisation means (I); the amount of actual energy (E) supplied to the vapourisation means during each use occasion; the amount of total energy (T) supplied to the

vapourisation means during each use occasion; and the cumulative amount of actual energy supplied to the vapourisation means (åE) during all previous uses of a liquid storage reservoir. Optionally, the liquid formulation reservoir is separable from the inhaler.

According to another aspect of the present invention, there is provided an inhaler capable of determining the amount of Active Pharmaceutical Ingredient (API) in a liquid formulation as defined herein and within a liquid storage reservoir usable with the inhaler, comprising a battery, a vaporisation means, an airflow sensor, a delivery controlling means, a

communication means, a feedback means and an information storage means.

According to another aspect of the present invention, there is provided a method of determining the amount of Active Pharmaceutical Ingredient (API) in a liquid formulation in a liquid storage reservoir successfully delivered to a user of an inhaler according to claim 8 over a time period comprising at least the steps of:

(i) measuring user inhalation airflow during a first use occasion of the inhaler to determine the portion of the inhalation above a threshold inhalation airspeed F1 ;

(ii) providing a pre-determined dose of API within an inhalable aerosol by supplying energy T to the vapourisation means upon sensing a threshold inhalation airspeed F1 ;

(iii) measuring the volume of air inhaled by the user during a first use occasion of the inhaler to determine the portion of inhalation occurring prior to a swept volume threshold V1 ;

(iv) determining the portion of the actual energy (E) supplied when user inhalation airflow is greater than a threshold F1 and prior to swept volume V1 ; and

(v) calculating the amount of API successfully delivered to the user using at least: the amount of energy determined in step (iv), the concentration of API within the liquid formulation, and the specific heat of vaporisation of the liquid formulation.

Optionally, the method further comprises the steps of:

(vi) determining the difference between the intended actual energy required for the complete pre-determined dose and the value determined in step (iv);

(vii) determining an amount of API unsuccessfully delivered to a user during a use occasion using at least: the amount of energy determined in step (vi), the concentration of API within the liquid formulation, and the specific heat of vaporisation of the liquid formulation; and (viii) instructing the inhaler to increase one or more subsequent doses of the API from the inhaler by the amount determined in step (vii).

Optionally, step (viii) comprises instructing the inhaler to deliver a subsequent dose of the API wholly or substantially equal to the amount determined in step (vii).

Optionally step (ii) comprises: (a) determining the initial energy (I) required to raise the temperature of the liquid formulation in the vapourisation means to its boiling point;

(b) determining the actual energy (E) required to vaporise the portion of the liquid formulation equivalent to the pre-determined inhalable aerosol dosage of the API; and

(c) determining the total energy (T) for the use occasion as the initial energy plus the actual energy (T=l+E).

Optionally, the determination of step (ii) includes one or more of the group selected from: the specific heat capacity of the vaporisation means, the specific heat capacity of the liquid formulation, the boiling point of the liquid formulation, the specific heat of vaporisation of the liquid formulation and the concentration of API within the liquid formulation.

Optionally, the determination of step (ii) includes determining the initial temperature of the vapourisation means.

According to another aspect of the present invention, there is provided a method of providing a pre-determined dose of an active pharmaceutical ingredient (API) in a liquid formulation within a liquid storage reservoir usable with an inhaler as defined herein, comprising at least the steps of:

(i) determining the initial energy (I) required to raise the temperature of the liquid formulation in the vapourisation means to its boiling point;

(ii) determining the actual energy (E) required to vaporise the portion of the liquid formulation equivalent to the pre-determined inhalable aerosol dosage of the API;

(iii) determining the total energy (T) for the use occasion as the initial energy of step (i) plus the actual energy of step (ii) (T=l+E); and

(iv) supplying the total energy (T) of step (iii) to the vapourisation means upon sensing a threshold inhalation airspeed (F1).

Optionally, step (i) further comprises determining one or more of the group selected from: the specific heat capacity of the vaporisation means, the specific heat capacity of the liquid formulation and the boiling point of the liquid formulation.

Optionally, step (i) further comprises determining the initial temperature of the vapourisation means. Optionally, step (ii) further comprises determining one or more of the group selected from: the specific heat of vaporisation of the liquid formulation and the concentration of API within said liquid formulation.

In another way, the present invention can provide a method of determining the actual energy (E) required to produce a pre-determined inhalable aerosol dosage of an API from a liquid formulation in an inhaler, comprising at least the steps of : (i) determining total energy (T) required to vaporise the pre-determined inhalable aerosol dosage of the API in the inhaler; (ii) determining initial energy (I) required to boil the liquid formulation in the inhaler; and (iii) calculating the actual energy from the total energy less the initial energy (E=T-I).

In another way, the present invention can provide apparatus capable of providing a dose of API as an inhalable aerosol to a user comprising a battery, a vaporisation means, a liquid formulation comprising the API in a reservoir, an airflow sensor, a delivery controlling means and an information storage means, wherein the delivery controlling means is able to deliver from the battery the total energy (T) required for the vaporiser to vaporise the liquid formulation to deliver the pre-determined inhalable aerosol dosage of the API, based on the initial energy (I) required to boil the liquid formulation in the inhaler, plus the actual energy (E) required after the initial energy to vaporise the portion of the liquid formulation required to deliver the pre-determined inhalable aerosol dosage of the API in the inhaler.

In another way, the present invention can provide a method of determining the total energy (T) required to vaporise a liquid formulation comprising an API in an inhaler to provide a pre determined inhalable aerosol dosage of API, comprising at least the steps of: (i) determining the initial energy (I) required to boil the liquid formulation in the inhaler; (ii) calculating the actual energy (E) required after step (i) to vaporise the portion of the liquid formulation required to deliver the pre-determined inhalable aerosol dosage of the API; and (iii) calculating the total energy (T) as the initial energy plus the actual energy (T=l+E).

In another way, the present invention can provide a method of preventing the production of undesirable chemicals from an inhaler comprising at least the steps of: i) Determining the theoretical maximum energy (M) required to vapourise all the liquid formulation within a liquid storage reservoir; ii) Summing the actual energy supplied (åE) during all previous use occasions of said liquid storage reservoir; iii) Calculating the difference between åE and M; and iv) Preventing the energisation of a vapourisation means within said liquid storage reservoir when the difference calculated in step (iii) is less than a minimum threshold energy value. In another way, the present invention can provide a method of calculating the amount of API within a liquid storage reservoir of an inhaler comprising at least the steps of: i) determining the theoretical maximum energy (M) required to vapourise all the liquid formulation within said liquid storage reservoir; ii) summing the actual energy supplied (åE) during all previous use occasions of said liquid storage reservoir; iii) calculating the difference between åE and M; and iv) calculating the amount of API using at least: the difference calculated in step (iii), the specific heat of vapourisation of the liquid media and the concentration of API within the liquid media.

In another way, the present invention can provide a method of calculating the amount of API successfully delivered to a user of a vaporising device over a time period, the method calculated by at least: (i) measuring user inhalation airflow during a first use occasion of the inhaler to determine the portion of the inhalation above an airspeed threshold F1 ; (ii) measuring the volume of air inhaled by the user during a first use occasion of the inhaler to determine the portion of inhalation occurring prior to a swept volume threshold V1 ; (iii) providing a pre-determined dose of API within an inhalable aerosol; (iv) determining the portion of the actual energy (E) supplied when user inhalation airflow is greater than a threshold F1 and prior to swept volume V1 ; (v) calculating the amount of API successfully delivered to the user using at least: the amount of energy determined in step (iv), the concentration of API within the liquid formulation and the specific heat of vaporisation of the liquid formulation.

In another way, the present invention can provide a method of determining the delivery of a dosage from an inhaler comprising at least the steps of: (i) measuring user inhalation airflow during a first use occasion of the inhaler to determine the portion of the inhalation above an airspeed threshold F1 ;

(ii) measuring the volume of air inhaled by the user during a first use occasion of the inhaler to determine the portion of inhalation occurring prior to a swept volume threshold V1 ; (iii) providing a pre-determined dose of API within an inhalable aerosol; (iv) determining the portion of the actual energy supplied when user inhalation airflow is greater than a threshold F1 and prior to swept volume V1 ; (v) calculating the amount of API successfully delivered to the user (P1) using at least: the amount of energy determined in step (iv), the concentration of API within the liquid formulation and the specific heat of vaporisation of the liquid formulation; (vi) determining the difference (P2) between the first pre-determined dose and the successful dose P1 calculated in step (v); and (vii) determining to increase one or more subsequent doses of the API from the inhaler to include the calculated portion P2 of step (vi).

In one embodiment, a method and apparatus for delivery of API within an inhalable aerosol is provided that includes at least: a battery, a vapourisation means, a liquid formulation reservoir, an airflow sensor, a control system and an information storage system. Such an apparatus: i) receives a dose instruction; ii) calculates the total amount of energy (T) required to deliver the dose; iii) energises the vapourisation means when user inhalation parameters are desirable; iv) calculates the amount of API delivered successfully to the user; v) records user compliance data including the amount of API delivered successfully and the timestamp of the use occasion.

In one embodiment, a method and apparatus for delivery of API within an inhalable aerosol is provided that includes at least: a battery, a vapourisation means, a liquid formulation reservoir, an airflow sensor, a control system and an information storage system. Such an apparatus: i) calculates the amount of API left within the liquid formulation reservoir, ii) displays the amount of API left within the reservoir using a feedback mechanism, iii) communicates the amount of API left within the reservoir to an external system.

In one embodiment, an apparatus for delivery of API within an inhalable aerosol is provided that includes at least: a battery, a vapourisation means, a liquid formulation reservoir, an airflow sensor, a control system and an information storage system. Such an apparatus verifies there is liquid formulation left within the reservoir before energising the vapourisation means to provide a dose of API within an inhalable aerosol.

In one embodiment, an apparatus for delivery of API within an inhalable aerosol is provided that includes at least: a battery, a vapourisation means, a liquid formulation reservoir, an airflow sensor, a control system and an information storage system. Such an apparatus calculates the amount of API provided by the apparatus during a use occasion.

In one embodiment, a method and apparatus for delivery of API within an inhalable aerosol is provided that controls the release of the API to a suitable window within the inhalation cycle by i) using one or more airflow sensors to detect inhalation of a suitable rate, ii) energising the vaporisation means to produce an inhalable aerosol from the liquid formulation, iii) stopping the production of inhalable aerosol should the inhalation parameters fall outside the suitable range. These and other features of the present invention, as well as the methods of operation and functions of the related elements, will become more apparent upon consideration of the following description and the appended claims with reference to the accompanying drawings, all of which form a part of this specification, wherein like reference numerals designate corresponding parts in various figures. It is to be expressly understood, however, that the drawings are for the purpose of illustration and description only and are not intended as a definition of the limits of the invention.

Figure 1 depicts graphically the relationship between energy supplied to the vapourisation means and the amount of API administered by the apparatus.

Figure 2 depicts graphically a typical user inhalation airflow over the course of a use occasion.

Figure 3 is an external three-dimensional view of the apparatus according to a particular embodiment.

Figure 4 is an external plan view of the apparatus according to a particular embodiment. Figure 5 is an external plan view of the apparatus according to a particular embodiment. Figure 6 is a cross-section through the apparatus showing the internal components.

Figure 7 is a cross-section through a particular embodiment of the liquid formulation reservoir.

Figures 8a and 8b are cross-sections through particular embodiments of vaporisation means.

Figure 9 is a block diagram showing diagrammatically the components of the apparatus. Figure 10 depicts the operational sequence for a particular embodiment of the apparatus.

Figure 1 shows how the amount of API administered is related to the amount of energy supplied into the apparatus of the present invention. The electrical energy entering the vapourisation means is converted to heat by the heat generative element. This heat has at least three outcomes: i) the temperature of the vapourisation means increases, ii) heat is lost to the surroundings iii) the liquid formulation is volatinised.

After a short initial lag period 103 the amount of API is directly proportional to the amount of energy supplied, i.e. a steady state system 104. The total energy (T) supplied to the vapourisation means during a use occasion 101 equals the sum of the initial energy (I) and the actual energy (E).

The lag period 103 relates to the initial energy (I) required to raise the temperature of the vapourisation means and liquid formulation therein to the boiling point of the liquid formulation. The initial energy required during the lag period 103 is a function of the thermal mass of the vapourisation means. Once the vapourisation means is at the boiling point of the liquid formulation essentially all the input energy into the system results in a transition from liquid to vapour under steady state conditions. Once in the vapour phase the API can be considered aerosolised and hence available for delivery.

A sufficiently characterised vapourisation means will have a repeatable lag period 103. The lag period and the initial energy (I) required to get to a steady state system can both be established experimentally. The initial (I) energy required to get to a steady state system can also be estimated from the thermal mass of the vapourisation means and liquid formulation contained therein.

The initial energy (I) required during lag period 103 is a function of the specific heat capacities of the heated components of the vapourisation means including at least: the heat generative means, a portion of the wicking material and a volume of liquid formulation and the temperature change. The temperature change of the vapourisation means during this lag period will be from ambient to the boiling point of the liquid formulation.

To reduce the complexity of the calculation it is preferable to use a vapourisation means with a constant resistance over operational range of temperature, suitable materials with include NiChrom.

To reduce the complexity of the calculation it is preferable to supply energy to the vapourisation means at a constant rate, pulse width modulation is a suitable means to achieve this.

To reduce the complexity of the calculation an estimate of ambient can be made at 20°C. For more accurate calculations a measurement of the starting temperature of the vapourisation means can be made. Temperature measurement can be made directly for example using a thermocouple. Temperature measurement can be made indirectly for example by using a heat generative element whose resistance changes with temperature.

The actual energy (E) required during the period 104 to vapourise the required dose of API within an inhalable aerosol can be determined by a calculation using at least: the concentration of API within the liquid formulation; the specific heat of vapourisation of the liquid formulation and the dose of API required. Hence the total energy (T) required to deliver a dose of API within a use occasion 101 can be determined from T = E + I. The apparatus of the present invention can accurately establish the amount of API provided as an inhalable aerosol during an individual use occasion by a calculation involving the actual energy (E) required to volatinise the liquid formulation during the steady state period 104. The actual energy (E) can be calculated by subtracting the initial energy (I) from the total energy supplied to the vapourisation means during the use occasion (T). The amount of API can be calculated from at least: the actual energy E, the concentration of API within the liquid formulation and the specific heat of vapourisation of the liquid formulation.

By summing the actual energy (åE) used during all use occasions of a specific liquid formulation reservoir and comparing to the theoretical maximum energy (M) required to vapourise all the liquid formulation within said reservoir, the apparatus can establish the amount of liquid formulation remaining within said reservoir after several use occasions. Using a similar method, the apparatus can also accurately establish the amount of API remaining within said liquid formulation reservoir at any point throughout the lifetime of the reservoir.

Preventing the energisation of the vapourisation means in the absence of liquid media is desirable to prevent“run-dry”. Without liquid media to evaporate, and thereby absorb the incoming energy, the vapourisation means will burn or char the materials of the wicking means producing undesirable taste and undesirable chemicals which can be inhaled.

By comparing the difference between the sum of the actual energy supplied during all previous use occasions of a reservoir and the theoretical maximum energy of said reservoir (M - åE) with a minimum threshold energy, the apparatus can determine to energise the vapourisation means only when there is liquid formulation present.

In an embodiment of the present invention, the delivery controlling means establishes the amount of API provided to a user during a use occasion by a calculation using at least: i) the thermal mass of the vaporisation means; ii) the specific heat of vaporisation of the liquid formulation; iii) the concentration of API within said liquid formulation, AND iv) a user minimum inhalation airflow rate being at least a pre-determined threshold F1.

In an alternate embodiment of the present invention, the delivery controlling means establishes the amount of API administered by a calculation using at least: the concentration of API within the liquid formulation and the length of time the vapourisation means is energised above a minimum user inhalation airflow threshold F1. In an embodiment of the present invention, the delivery controlling means establishes the amount of API successfully administered to a user during a use occasion by a calculation using at least: i) the concentration of API within the liquid formulation, ii) the heat of vapourisation of the liquid formulation, iii) the amount of actual energy supplied to the vapourisation means (E); iv) a user minimum inhalation airflow rate being at least a pre determined threshold F1 ; and v) a threshold swept volume V1.

In an embodiment of the present invention a method of enhancing user compliance with a prescribed dosage regime is provided that comprises at least the steps of: providing a pre determined dose of API for a first use occasion; calculating the amount of dose unsuccessfully delivered during the first use occasion; adjusting a least one subsequent dose.

In an embodiment of the present invention a method of enhancing user compliance with a prescribed dosage regime is provided that further comprises increasing a least one subsequent dose by up to the amount of dose unsuccessfully delivered during the first use occasion.

In an alternate embodiment of the present invention a method of enhancing user compliance with a prescribed dosage regime is provided that further comprises providing a subsequent dose of API equal to or less than the amount of unsuccessfully delivered dose from the first use occasion.

Figure 2 depicts a typical user inhalation airflow during a use occasion. 105 is the threshold inhalation airflow F1 to sufficiently entrain the inhalable aerosol. 106 indicates the area under the graph that represents the volume of air V1 required to adequately sweep the aerosol into the aveoli. Region 107 represents the portion of the inhalation cycle which is most desirable for effective API delivery to the user.

The portion of the dose P1 administered within region 107 is considered successfully delivered to the user. Any portion of the dose P2 administered outside region 107 is considered unsuccessfully delivered to the user.

Threshold inhalation rate F1 is defined as an airflow rate sufficient to entrain the inhalable aerosol produced by the device and carry the aerosol into the lung to be deposited within the alveoli where the active ingredients can be absorbed into the blood stream. Threshold inhalation rate F1 is greater than 0.01 litres per second as measured on a spirometer. Preferably a threshold inhalation rate F1 is greater than 0.05 litres per second. More preferably a threshold inhalation rate F1 is greater than 0.1 litres per second.

Swept volume V1 is defined as a volume of air equivalent to the upper respiratory tract of the user. This volume depends on the user anatomy being greater for those with larger thoracic cavity, e.g. adults typically have greater volume than children. V1 can be in the range 100 to 2000ml, more preferable V1 is in the range 500 to 1500ml, more preferably V1 is in the range 750ml to 1250ml.

Figures 3, 4 and 5 show the main external components of the apparatus according to particular embodiments of the present invention. The apparatus 1 is comprised of a main body 2 and a removable liquid formulation reservoir 3. The mouth end 6. Figure 4 shows the user activated element as a button 5 and the feedback mechanism as an array of LED lights 4. Figure 5 shows an alternative embodiment where the user activated element is a removable cap 8 and the feedback mechanism is an LCD display 7.

Figure 6 shows the main internal components of the apparatus: battery 12, delivery controlling means 13, information storage means 14, communication means 15, vibration motor 16 for haptic feedback, microphone 17 for audible feedback and liquid formulation 20. Figure 6 also shows the outer housing of the device 9 with an air inlet 10 and an air outlet 11 where the user inhales the inhalable aerosol. The pathway for air through the device 19 includes: air inlet 10, airflow sensor 18, vaporisation means 21 , air outlet 11.

Figure 7 shows more detail of the liquid formulation reservoir 3 which comprises a plastic body 24, a liquid formulation 20 to be volatilised, a heat generative element 23 and a wicking means 22.

Figures 8a and 8b show more detail of specific embodiments of the vaporisation means 21 highlighting the airflow path 19, the heat generative element 23 and the wicking means 22. In figure 8a, the airflow path 19 runs over and is perpendicular to the main axis of the heat generative element 23 which is wrapped around the wicking means 22. In figure 8b the airflow path 19 runs through and is parallel to the main axis of the heat generative element 23 and the wicking means 22 is in the form of a hollow cylinder that surrounds the heat generative element 23. The term aerosol shall be interpreted to include gas, vapour, droplets, condensates, particulates and combinations thereof. An inhalable aerosol shall mean an aerosol with an average particle size as measured by laser dispersion ranging from 0.1 to 10 pm, more preferably 0.1 to 1.5 pm.

Liquid formulation 20 shall be interpreted to include liquids, mixtures, solutions, suspensions, micelles, gels, foams, mousses and combinations thereof. Additionally, the liquid formulation can be contained within a matrix, absorbed within a matrix or adsorbed onto a matrix and combinations thereof. Suitable matrices include absorbent fabrics such as cotton or glass wool and solid adsorbents such as zeolites and other inorganic clays.

Battery 12 shall be interpreted as any means of storing an electrical charge including metal- acid accumulators, cells based on zinc, nickel or lithium wherein the electrolyte is liquid, solid or polymeric in nature. Alternatively, a capacitor can also be used as a means of storing electrical charge. Of particular relevance to the present invention are lithium-polymer rechargeable batteries such as those based on lithium iron phosphate and lithium manganese oxide.

A vaporisation means 21 shall be interpreted to be any means of converting the liquid formulation 20 into an aerosol. In a preferred embodiment, the vaporisation means 21 utilises a heat generative element 23 to generate heat energy which converts the liquid formulation into a vapour. This vapour subsequently condenses to form droplets which are suitable for inhalation. The heat generative element 23 converts electrical energy derived from the battery 12 into heat. Heat is produced as a result of the resistive nature of the heat generative element. The heat generative element 23 can be composed of a resistive metal such as titanium and stainless steel or a metal alloy and combinations thereof. Preferably the heat generative element contains the alloy NiChrom which is desirable as it has a constant resistance at a range of temperatures. Alternatively, the heat generative element 23 can be composed of a resistive ceramic such as those based on alumina or silicon nitride.

A vaporisation means 21 is further characterised by being in fluid connection with the liquid formulation 20 to provide a supply of liquid for vaporisation. The connection between the vaporisation means 21 and the liquid formulation 20 is by a wicking means 22 such as a wick, capillary system or tube capable of transferring liquid. Of particular relevance to the present invention are materials that interact with the liquid formulation by capillary action. Such materials act both to transfer liquid to the heat generative means by forming a continuous liquid path and act as a barrier to prevent undesirable liquid leakage from the device due to their ability to retain liquid within their structure.

An airflow sensor 18 is any system capable of detecting the movement of air through the device and providing an electrical communication to the delivery controlling means 13. Airflow sensor 18 can be interpreted to mean a single sensor or multiple sensors. In an embodiment of the present invention one sensor is used to detect an air flow rate and a second sensor detect a higher air flow rate, the combination of both sensor outputs is then used to determine air flow within a desirable range. Additional air flow ranges can be determined by the appropriate use of different sensing levels with one or more sensors. A preferred embodiment utilises a single sensor with multiple sensing thresholds that can provide electrical communication corresponding to the different air flows. An airflow sensor can measure airflow using a rotating vane anemometer, a moving vane meter, a hot-wire detector, a Karman vortex sensor, an electromechanical membrane sensor, MEMS technology or combinations thereof.

A preferred embodiment of the present invention utilises an airflow sensor 18 containing a capacitive microphone to detect air flow. The flow of air through a device alters air pressure and generates turbulence which deflects a charged diaphragm within a microphone causing a change in capacitance. The change in capacitance is detected electronically and used to generate a communications signal to the delivery controlling means.

An alternative preferred embodiment of the present invention utilises a MEMS pressure sensor as an airflow sensor 18. The action of the user inhaling through the apparatus causes a reduction in air pressure which is converted into an electrical signal by the MEMS sensor and the signal is passed to the delivery controlling means. Higher flow rates cause a greater reduction in air pressure, hence within a defined airflow pathway such MEMS sensor can be accurately calibrated to measure user inhalation air flow.

A user activated element 5, 8 is a means by which a user can interact with the device to bring a change from sleep mode to active mode. Preferably a user activated element is a means to alter an electrical circuit such which communicates with the delivery controlling means to activate the device. A user activated means may be a button, switch, lever, contacts, touch switch reliant upon capacitance, resistance or piezo or combination thereof. Preferably a user activated element is a depressible button 5. It is advantageous that the design of the user activated element prevents accidental activation or activation by a minor. Such accidental activation can be prevented by using mechanically complexity or more preferably by requiring a particular sequence of button presses such as five presses within two seconds to cause activation.

In an alternative preferred embodiment, a user activated element is a physical barrier which prevents use of the device unless moved. The action of moving the physical barrier from its resting position is preferably linked to the actuation of an electrical means which communicates with the delivery controlling means. The physical barrier can be separable from the device or be conjoined via a joining element. A separable user activated element can be a removable case, housing or sleeve. In an alternative embodiment, the physical barrier is mechanically complex which is useful to prevent unintended usage of the device by minors such as a cap 8 which can be child resistant.

A delivery controlling means 13 shall be interpreted as electronic circuity which can respond to communication signals from the airflow sensor 18, activate the vaporisation means 21 and alter the state of the feedback mechanism 4, 7. Additionally, a delivery controlling means can also respond to a communication signal from the user activated element 5, 8. Additionally, a delivery controlling means can also activate the airflow sensor 18. A delivery controlling means 13 typically utilises at least one microprocessor to process the communications, perform calculations, actuate elements and alter the feedback mechanism.

In an embodiment of the present invention the delivery controlling means interacts with a removable liquid formulation reservoir and thereby modifies at least one vaporisation parameter including temperature, time, duration and combinations thereof, the relevant parameters being stored within an information storage means 14a within the removable liquid formulation reservoir, in a library referenced by the delivery controlling means or combinations thereof.

A delivery controlling means 13 can be in communication with an information storage means 14, 14a. Preferably an information storage means is a solid-state memory. The information storage means can be part of the main apparatus body 14. The information storage means can be part of the liquid formulation reservoir 14a. Preferably both the main apparatus body and the liquid formulation reservoir each contain an information storage means.

Preferably the delivery controlling means can communicate externally to provide electronic feedback via a plug-in wired interface using a standard protocol such as USB. Preferably the delivery controlling means can communicate externally using a communication means 15 using means such as Bluetooth, WiFi, LoRA, radiowave, microwave, infra-red and combinations thereof to provide wireless feedback. Preferably external communications are two-way providing data to the external system and receiving data from the external system.

Data to be provided by the delivery controlling means to the external system includes use events and device information. A use event means any interaction between the user and the device relevant to the purpose of the invention and any resultant event caused by that action. A use event includes removal of a cap, insertion of a liquid formulation reservoir, actuation of a user activated element, inhalation, achievement of the suitable inhalation flow rate, achievement of the desired duration of inhalation, activation of the vaporisation means, status of feedback mechanism, successful delivery of API, unsuccessful delivery of API, amount of pre-determined dose successfully delivered; amount of pre-determined dose unsuccessfully delivered and combinations thereof. Device information includes identifiers and version numbers of device hardware, firmware, software; identifiers for removable liquid formulation reservoir; amount of battery capacity and liquid formulation used and remaining, fault codes, system status, system time and combinations thereof.

Data to be received by the delivery controlling means from the external system would include prescription information, prescribed dosage regimes, software updates, firmware updates, fault diagnosis, fault resetting, system resetting, information regarding the liquid formulation and the liquid formulation reservoir, parameters for vaporisation and combinations thereof.

In an embodiment of the present invention the delivery controlling means receives instructions from an external system and thereby modifies at least one vaporisation parameter including temperature, time, duration, delay and combinations thereof.

A communication means can communicate the amount of API successfully delivered during a use occasion to an external system. A communication means can communicate the amount of API unsuccessfully delivered during a use occasion to an external system.

A feedback mechanism is any means for the device to communicate with the user to confirm or indicate device status including visual, auditory, haptic means and combinations thereof. A feedback mechanism has at least two states that the delivery controlling means switches between. More preferably a feedback mechanism has multiple states that can be activated by the delivery controlling means. Preferably the feedback means comprises at least two of visual means, audible means and haptic means. A feedback means can provide feedback to the patient to indicate suitable inhalation rate achieved and suitable inhalation duration achieved using a feedback mechanism. A feedback means can provide feedback on the amount of API successfully delivered during a use occasion. A feedback means can provide feedback on the residual amount of API unsuccessfully delivered during a use occasion.

An embodiment of the present invention comprises an apparatus and method for enhancing user compliance with a prescribed dosage regime comprises at least a battery, a vapourisation means, a liquid formulation reservoir, an airflow sensor, a delivery controlling means, an information storage means, a feedback means and a communication means.

A preferred embodiment of the present invention uses at least one light emitting diode 4 (LED) to provide visual feedback. The multiple states for visual feedback include turning on, turning off, change in intensity, change in colour of the at least one LED and combinations thereof. In a preferred embodiment, more than one LED is used to provide visual feedback. An alternative embodiment uses at least one liquid crystal display 7 (LCD) to provide visual feedback, more preferably an array of LCD such as a seven segment LCD which can be used to display alpha numeric characters. Alternate display technologies such as those found in consumer electronic apparatus can also be used to provide visual feedback.

An alternate preferred embodiment of the present invention uses at least one speaker 17 to produce audible feedback. The multiple states for audible feedback include turning on, turning off, change in intensity, change in pitch of sound emitted, verbal messages, and combinations thereof.

An alternate preferred embodiment of the present invention uses at least one vibration motor 16 to produce haptic feedback. The multiple state for haptic feedback include turning on, turning off, change in intensity, change in pitch of vibrations emitted and combinations thereof.

More preferably the feedback mechanism uses visual feedback and at least one other feedback means such as audible or haptic or both. This is useful for visually impaired users.

The term active pharmaceutical ingredient (API) shall be interpreted as any chemical which has a pharmacological or sensorial effect. The terms drug and medicament are hereby included within this definition of API. Optionally the API may comprise tobacco, extracts of tobacco (by water or organic solvent), nicotine, taurine, clove and combinations thereof.

Optionally the API may comprise: cetirizine, pseudoephedrine, ibuprofen, naproxen, omeprazole, doxylamine, diphenhydramine, melatonin, or meclizine and combinations thereof.

Optionally the API may comprise: albuterol, levalbuterol, pirbuterol, salmeterol, formoterol, atropine sulfate, ipratropium bromide, fluticasone, budesonide, mometasone, montelukast, zafirlukast, theophylline or combinations thereof.

Optionally the API may comprise: a polyphenol, a green tea catechin, caffeine, a phenol, a glycoside, a labdane diterpenoid, yohimbine, a proanthocyanidin, terpene glycoside, an omega fatty acid, echinacoside, an alkaloid, isovaleric acid, a terpene, gamma-aminobutyric acid, a senna glycoside, cinnamaldehyde, Vitamin D or combinations thereof.

Optionally the API may comprise organic material from a Cannabis genus plant, an extract from a Cannabis genus plant, a cannabinoid or combinations thereof. The API may comprise tetrahydrocannabinol (THC), carmabigerolic acid, cannabigerol, tetrahydrocannabinolic acid, cannabichromene, cannabicyclol, cannabivarin, cannabichromevarin, cannabigerovarin, cannabigerol monomethyl ether, delta-8- tetrahydrocannabinol, delta-9-tetrahydrocannabinol, tetrahydrocannabivarin, cannabinolic acid, cannabinol, cannabidiolic acid, cannabidivaric acid, cannabidiol (CBD), cannabichromenic acid, cannabichromene, cannabicyclolic acid or combinations thereof.

In a preferred embodiment the API is CBD. In an alternative embodiment the API is THC. In an alternative embodiment the API is a combination of THC and CBD.

In a preferred embodiment of the present invention the outer body of the device 9 is made of acrylonitrile butadiene styrene plastic; the airflow sensor 18 is a Pressure sensor by ST Micro; the battery 12 is a lithium polymer cell 3.7v 840mAh by YOK; the feedback mechanism 4 is an array of four LEDs and a vibration motor 16; the liquid formulation 20 is a 1 millilitre solution of 200mg per millilitre CBD in a 80:20 mix of propylene glycol and glycerine; the vaporisation means 21 comprises a heat generative element 23 composed of Nichrome wire of resistance 2ohm, wrapped helically around a central glass fibre wick 22 separated from the liquid formulation 20 by a pad of cotton wicking material; the body of the liquid formulation reservoir 24 is made of polyethylene terephthalate; the user activated element 5 is a push-to-make depressible button; the delivery controlling means 13, communication means 15 and information storage means 14 are an integrated unit based on a Nordic Semiconductor Bluetooth SOC and an Atmel 8bit AVR Microcontroller. The removable liquid formulation reservoir 3 contains an embedded EEPROM based ID tag from Microchip as an information storage means 14a. The electronic circuits are completed using appropriate components and coded appropriately by those skilled in the art.

In this preferred embodiment, the desirable inhalation threshold F1 is set at 0.025 litres per second and the desirable swept volume V1 is set at 250ml.

Following the flow diagram depicted in figure 10, in this preferred embodiment, the user activates the apparatus 1 using button 5.

The delivery controlling means 13 retrieves the dose instructions from the information storage means 14.

The delivery controlling means 13 determines if there is API remaining within the liquid formulation reservoir by interrogating the information storage means 14a to establish if (M- åE) is greater than zero. M is previously calculated from the volume of liquid formulation within the reservoir 3 and the specific heat of vapourisation of said liquid and the value stored on the information storage means 14a.

The delivery controlling means 13 retrieves information pertaining to the liquid formulation reservoir from the information storage means 14a. The retrieved information includes: the concentration of API within the liquid formulation, the specific heat of vapourisation of the liquid formulation and the initial energy (I). The initial energy (I) has previously been established by a calibration measurement of the vapourisation means within the liquid formulation reservoir and the measure value stored on the information storage means 14a.

The delivery controlling means 13 calculates the amount of actual energy required E. Actual energy (E) = required dose of API multiplied by the specific heat of vapourisation of the liquid formulation divided by the concentration of API within the liquid formulation.

The delivery controlling means 13 calculates the amount of total energy required (T). Total energy (T) = actual energy (E) plus initial energy (I). Upon sensing user inhalation airflow greater than desired threshold F1 the vapourising means 21 is energised and an inhalable aerosol is produced from the liquid formulation 20. Provided the inhalation airflow remains greater than F1 , the delivery controlling means continues to supply energy to the vapourisation means until the total amount of energy supplied is equal to the total energy T calculated. Should the airflow fall below F1 the supply of energy is discontinued. After the supply of energy is finished, the airflow sensor 18 continues to measure user inhalation airflow until the end of the use occasion.

Upon completion of the use occasion, the delivery controlling means 13 adds the actual energy E supplied during this use occasion to that supplied during all previous use occasions and updates the register for åE in the information storage means 14a.

The amount of API remaining within the liquid formulation reservoir is calculated by dividing (M-åE) by the specific heat of vapourisation of the liquid formulation and multiplying by the concentration of API within the liquid formulation. The amount of API remaining is displayed to the user as percentage of a full reservoir via the feedback means 4 as 0-25% (1 LED), 25- 50% (2 LED), 50-75% (3 LED) or 75-100% (4 LED).

In this preferred embodiment, the delivery controlling means 13 determines the portion of the actual energy supplied to the vapourisation means during the period when inhalation flow rate is greater than F1 and with a swept volume greater than V1 ; the delivery controlling means 13 calculates the amount of API successfully administered to the user and records this data alongside date and time. This use data is stored on the information storage means 14.

In this preferred embodiment, the delivery controlling means 13 captures data relating to the date, time and characteristics of each use event, device and liquid formulation reservoir identities, stores it using the information storage means 14 makes the data available via the communication means 15 to an external system via Bluetooth once a connection becomes available.

In this preferred embodiment the delivery controlling means also stores use event data on the information storage means 14a within the liquid formulation reservoir 3.

Although the invention has been described in detail for the purpose of illustration based on what is considered to be the most practical and preferred embodiment, it is to be understood that such detail is solely for that purpose and that the invention is not limited to the disclosed embodiments, but, on the contrary, it is intended to cover modifications and equivalent arrangements that are within the scope of the appended claims. For example, it is to be understood that the present invention contemplates that, to the extent possible, one or more features of any embodiment can be combined with one or more features of any other embodiment.

Claims

1. A method of determining the amount of Active Pharmaceutical Ingredient (API) in a liquid formulation within a liquid storage reservoir usable with an inhaler with a liquid vapourisation means, and following a plurality of use occasions of the liquid storage reservoir, comprising at least the steps of:

(iii) determining the difference between M and åE; and

(iv) determining the amount of API in the liquid storage reservoir using at least: the difference calculated in step (iii), the specific heat of vapourisation of the liquid formulation, and the concentration of API within the liquid formulation.

2. A method according to claim 1 further comprising the step of indicating or communicating the amount API determined in step (iv) either to a user using a feedback means, or to an external system using a communication means, or both.

3. A method according to claim 1 or claim 2 further comprising the step of preventing the energisation of the vapourisation means when the difference in energy calculated in step (iii) is less than a pre-determined threshold energy value.

4. A method according to any one of claims 1-3 wherein step (ii) comprises: (a) determining the total energy (T) supplied to the vapourisation means during a previous use occasion;

5. A method according to claim 4 wherein the determination of one or more of total energy (T), initial energy (I) and actual energy (E) utilises one or more of the group selected from: the thermal mass of the vaporisation means, the boiling point of the liquid formulation, the specific heat capacity of the liquid formulation, the specific heat of vaporisation of the liquid formulation, and the concentration of API within the liquid formulation.

6. A method according to any preceding claim further comprising storing in an information storage means within the inhaler or within the liquid formulation reservoir, one or more of the group selected from: the thermal mass of the vapourisation means; the specific heat of vapourisation per unit volume of liquid formulation; the concentration of API within the liquid formulation; the boiling point of the liquid formulation; the total energy required to vapourise fully the liquid formulation contained within the liquid storage reservoir (M); the amount of initial energy for the vapourisation means (I); the amount of actual energy (E) supplied to the

vapourisation means during each use occasion; the amount of total energy (T) supplied to the vapourisation means during each use occasion; and the cumulative amount of actual energy supplied to the vapourisation means (åE) during all previous uses of a liquid storage reservoir.

7. A method according to any preceding claim wherein the liquid formulation reservoir is separable from the inhaler.

8. An inhaler capable of determining the amount of Active Pharmaceutical Ingredient (API) in a liquid formulation as defined in any one of claims 1-7 and within a liquid storage reservoir usable with the inhaler, comprising a battery, a vaporisation means, an airflow sensor, a delivery controlling means, a communication means, a feedback means and an information storage means.

9. A method of determining the amount of Active Pharmaceutical Ingredient (API) in a liquid formulation in a liquid storage reservoir successfully delivered to a user of an inhaler according to claim 8 over a time period comprising at least the steps of:

(i) measuring user inhalation airflow during a first use occasion of the inhaler to determine the portion of the inhalation above a threshold inhalation airspeed F1 ; (ii) providing a pre-determined dose of API within an inhalable aerosol by supplying energy T to the vapourisation means upon sensing a threshold inhalation airspeed

F1 ;

10. A method according to claim 9 further comprising the steps of:

(vii) determining an amount of API unsuccessfully delivered to a user during a use occasion using at least: the amount of energy determined in step (vi), the

concentration of API within the liquid formulation, and the specific heat of vaporisation of the liquid formulation; and

(viii) instructing the inhaler to increase one or more subsequent doses of the API from the inhaler by the amount determined in step (vii).

11. A method according to claim 10 wherein step (viii) comprises instructing the inhaler to deliver a subsequent dose of the API wholly or substantially equal to the amount determined in step (vii).

12. A method according to any one of claims 9-11 wherein step (ii) comprises:

(a) determining the initial energy (I) required to raise the temperature of the liquid formulation in the vapourisation means to its boiling point;

13. A method according to any one of claims 9-12 wherein the determination of step (ii) includes one or more of the group selected from: the specific heat capacity of the vaporisation means, the specific heat capacity of the liquid formulation, the boiling point of the liquid formulation, the specific heat of vaporisation of the liquid formulation and the concentration of API within the liquid formulation.

14. A method according to any one claims 9-13 wherein the determination of step

(ii) includes determining the initial temperature of the vapourisation means.

15. A method of providing a pre-determined dose of an active pharmaceutical ingredient (API) in a liquid formulation within a liquid storage reservoir usable with an inhaler as defined in claim 8, comprising at least the steps of:

16. A method according to claim 15 wherein step (i) further comprises determining one or more of the group selected from: the specific heat capacity of the vaporisation means, the specific heat capacity of the liquid formulation and the boiling point of the liquid formulation.

17. A method according to claim 15 or claim 16 wherein step (i) further comprises determining the initial temperature of the vapourisation means.

18. A method according to any one of claims 15-17 wherein step (ii) further comprises determining one or more of the group selected from: the specific heat of vaporisation of the liquid formulation and the concentration of API within said liquid formulation.